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  • Articles  (396)
  • Protein Structure, Tertiary  (396)
  • 2005-2009  (396)
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  • Articles  (396)
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  • 1
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    Pore architecture and ion sites in acid-sensing ion channels and P2X receptors (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-31
    Description: Acid-sensing ion channels are proton-activated, sodium-selective channels composed of three subunits, and are members of the superfamily of epithelial sodium channels, mechanosensitive and FMRF-amide peptide-gated ion channels. These ubiquitous eukaryotic ion channels have essential roles in biological activities as diverse as sodium homeostasis, taste and pain. Despite their crucial roles in biology and their unusual trimeric subunit stoichiometry, there is little knowledge of the structural and chemical principles underlying their ion channel architecture and ion-binding sites. Here we present the structure of a functional acid-sensing ion channel in a desensitized state at 3 A resolution, the location and composition of the approximately 8 A 'thick' desensitization gate, and the trigonal antiprism coordination of caesium ions bound in the extracellular vestibule. Comparison of the acid-sensing ion channel structure with the ATP-gated P2X(4) receptor reveals similarity in pore architecture and aqueous vestibules, suggesting that there are unanticipated yet common structural and mechanistic principles.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845979/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzales, Eric B -- Kawate, Toshimitsu -- Gouaux, Eric -- F32 GM083615/GM/NIGMS NIH HHS/ -- F32 GM083615-01/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 30;460(7255):599-604. doi: 10.1038/nature08218.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641589" target="_blank"〉PubMed〈/a〉
    Keywords: Acid Sensing Ion Channels ; Animals ; Binding Sites ; CHO Cells ; Cell Line ; Cesium/metabolism ; Chickens/*physiology ; Cricetinae ; Cricetulus ; Crystallization ; Humans ; Ions/metabolism ; *Models, Molecular ; Nerve Tissue Proteins/*chemistry ; Protein Structure, Tertiary ; Receptors, Purinergic P2/*chemistry ; Receptors, Purinergic P2X ; Sodium Channels/*chemistry ; Zebrafish/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Crystal structure of the ATP-gated P2X(4) ion channel in the closed state (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-31
    Description: P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X(4) receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in beta-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the 'gate' is defined by an approximately 8 A slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720809/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawate, Toshimitsu -- Michel, Jennifer Carlisle -- Birdsong, William T -- Gouaux, Eric -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM075026-04/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 30;460(7255):592-8. doi: 10.1038/nature08198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641588" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Gadolinium/metabolism ; Humans ; Ion Channels/antagonists & inhibitors/*chemistry ; Membrane Proteins/chemistry ; *Models, Molecular ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Purinergic P2 Receptor Antagonists ; Receptors, Purinergic P2/*chemistry ; Receptors, Purinergic P2X4 ; Zebrafish/*physiology ; Zebrafish Proteins/antagonists & inhibitors/*chemistry
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Riboflavin kinase couples TNF receptor 1 to NADPH oxidase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-31
    Description: Reactive oxygen species (ROS) produced by NADPH oxidase function as defence and signalling molecules related to innate immunity and various cellular responses. The activation of NADPH oxidase in response to plasma membrane receptor activation depends on the phosphorylation of cytoplasmic oxidase subunits, their translocation to membranes and the assembly of all NADPH oxidase components. Tumour necrosis factor (TNF) is a prominent stimulus of ROS production, but the molecular mechanisms by which TNF activates NADPH oxidase are poorly understood. Here we identify riboflavin kinase (RFK, formerly known as flavokinase) as a previously unrecognized TNF-receptor-1 (TNFR1)-binding protein that physically and functionally couples TNFR1 to NADPH oxidase. In mouse and human cells, RFK binds to both the TNFR1-death domain and to p22(phox), the common subunit of NADPH oxidase isoforms. RFK-mediated bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but not for Toll-like-receptor-induced ROS production. Exogenous flavin mononucleotide or FAD was able to substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient cells. RFK is rate-limiting in the synthesis of FAD, an essential prosthetic group of NADPH oxidase. The results suggest that TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yazdanpanah, Benjamin -- Wiegmann, Katja -- Tchikov, Vladimir -- Krut, Oleg -- Pongratz, Carola -- Schramm, Michael -- Kleinridders, Andre -- Wunderlich, Thomas -- Kashkar, Hamid -- Utermohlen, Olaf -- Bruning, Jens C -- Schutze, Stefan -- Kronke, Martin -- England -- Nature. 2009 Aug 27;460(7259):1159-63. doi: 10.1038/nature08206. Epub 2009 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cytochrome b Group/metabolism ; Enzyme Activation ; Fibroblasts ; Flavin Mononucleotide/metabolism ; Flavin-Adenine Dinucleotide/biosynthesis/metabolism ; HeLa Cells ; Humans ; Isoenzymes/chemistry/metabolism ; Membrane Glycoproteins/metabolism ; Mice ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidase/chemistry/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/deficiency/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor, Type I/chemistry/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-03-06
    Description: Osmoregulated transporters sense intracellular osmotic pressure and respond to hyperosmotic stress by accumulation of osmolytes to restore normal hydration levels. Here we report the determination of the X-ray structure of a member of the family of betaine/choline/carnitine transporters, the Na(+)-coupled symporter BetP from Corynebacterium glutamicum, which is a highly effective osmoregulated uptake system for glycine betaine. Glycine betaine is bound in a tryptophan box occluded from both sides of the membrane with aromatic side chains lining the transport pathway. BetP has the same overall fold as three unrelated Na(+)-coupled symporters. Whereas these are crystallized in either the outward-facing or the inward-facing conformation, the BetP structure reveals a unique intermediate conformation in the Na(+)-coupled transport cycle. The trimeric architecture of BetP and the break in three-fold symmetry by the osmosensing C-terminal helices suggest a regulatory mechanism of Na(+)-coupled osmolyte transport to counteract osmotic stress.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ressl, Susanne -- Terwisscha van Scheltinga, Anke C -- Vonrhein, Clemens -- Ott, Vera -- Ziegler, Christine -- England -- Nature. 2009 Mar 5;458(7234):47-52. doi: 10.1038/nature07819.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Biophysics, Department of Structural Biology, 60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262666" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics/*metabolism ; Betaine/*metabolism ; Binding Sites ; Carrier Proteins/*chemistry/genetics/*metabolism ; Corynebacterium glutamicum/*chemistry/genetics ; Crystallography, X-Ray ; Ion Transport ; Models, Molecular ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Sodium/*metabolism ; Structure-Activity Relationship
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Rational design of a structural and functional nitric oxide reductase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-27
    Description: Protein design provides a rigorous test of our knowledge about proteins and allows the creation of novel enzymes for biotechnological applications. Whereas progress has been made in designing proteins that mimic native proteins structurally, it is more difficult to design functional proteins. In comparison to recent successes in designing non-metalloproteins, it is even more challenging to rationally design metalloproteins that reproduce both the structure and function of native metalloenzymes. This is because protein metal-binding sites are much more varied than non-metal-containing sites, in terms of different metal ion oxidation states, preferred geometry and metal ion ligand donor sets. Because of their variability, it has been difficult to predict metal-binding site properties in silico, as many of the parameters, such as force fields, are ill-defined. Therefore, the successful design of a structural and functional metalloprotein would greatly advance the field of protein design and our understanding of enzymes. Here we report a successful, rational design of a structural and functional model of a metalloprotein, nitric oxide reductase (NOR), by introducing three histidines and one glutamate, predicted as ligands in the active site of NOR, into the distal pocket of myoglobin. A crystal structure of the designed protein confirms that the minimized computer model contains a haem/non-haem Fe(B) centre that is remarkably similar to that in the crystal structure. This designed protein also exhibits NO reduction activity, and so models both the structure and function of NOR, offering insight that the active site glutamate is required for both iron binding and activity. These results show that structural and functional metalloproteins can be rationally designed in silico.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297211/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297211/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeung, Natasha -- Lin, Ying-Wu -- Gao, Yi-Gui -- Zhao, Xuan -- Russell, Brandy S -- Lei, Lanyu -- Miner, Kyle D -- Robinson, Howard -- Lu, Yi -- GM062211/GM/NIGMS NIH HHS/ -- R01 GM062211/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1079-82. doi: 10.1038/nature08620. Epub 2009 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940850" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallization ; Iron/metabolism ; Models, Molecular ; Myoglobin/chemistry ; Nitric Oxide/metabolism ; Oxidoreductases/*chemical synthesis/*chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary
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  • 6
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    Transport mechanism of a bacterial homologue of glutamate transporters (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-20
    Description: Glutamate transporters are integral membrane proteins that catalyse a thermodynamically uphill uptake of the neurotransmitter glutamate from the synaptic cleft into the cytoplasm of glia and neuronal cells by harnessing the energy of pre-existing electrochemical gradients of ions. Crucial to the reaction is the conformational transition of the transporters between outward and inward facing states, in which the substrate binding sites are accessible from the extracellular space and the cytoplasm, respectively. Here we describe the crystal structure of a double cysteine mutant of a glutamate transporter homologue from Pyrococcus horikoshii, Glt(Ph), which is trapped in the inward facing state by cysteine crosslinking. Together with the previously determined crystal structures of Glt(Ph) in the outward facing state, the structure of the crosslinked mutant allows us to propose a molecular mechanism by which Glt(Ph) and, by analogy, mammalian glutamate transporters mediate sodium-coupled substrate uptake.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934767/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934767/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reyes, Nicolas -- Ginter, Christopher -- Boudker, Olga -- R01 NS064357/NS/NINDS NIH HHS/ -- R01 NS064357-01A1/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Dec 17;462(7275):880-5. doi: 10.1038/nature08616. Epub 2009 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Box 75, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924125" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Transport System X-AG/*chemistry/genetics/*metabolism ; Binding Sites ; Biological Transport ; Cross-Linking Reagents ; Crystallography, X-Ray ; Cysteine/genetics/metabolism ; Models, Molecular ; Movement ; Mutant Proteins/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Pyrococcus horikoshii/*chemistry ; Sodium/metabolism ; Structure-Activity Relationship
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  • 7
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    A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-10
    Description: Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved beta-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810868/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Melcher, Karsten -- Ng, Ley-Moy -- Zhou, X Edward -- Soon, Fen-Fen -- Xu, Yong -- Suino-Powell, Kelly M -- Park, Sang-Youl -- Weiner, Joshua J -- Fujii, Hiroaki -- Chinnusamy, Viswanathan -- Kovach, Amanda -- Li, Jun -- Wang, Yonghong -- Li, Jiayang -- Peterson, Francis C -- Jensen, Davin R -- Yong, Eu-Leong -- Volkman, Brian F -- Cutler, Sean R -- Zhu, Jian-Kang -- Xu, H Eric -- R01 DK066202/DK/NIDDK NIH HHS/ -- R01 DK066202-04/DK/NIDDK NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 DK071662-05/DK/NIDDK NIH HHS/ -- R01 GM087413/GM/NIGMS NIH HHS/ -- R01 GM087413-01/GM/NIGMS NIH HHS/ -- R01 HL089301/HL/NHLBI NIH HHS/ -- R01 HL089301-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Dec 3;462(7273):602-8. doi: 10.1038/nature08613.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, Michigan 49503, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898420" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Arabidopsis/genetics/metabolism/*physiology ; Arabidopsis Proteins/*chemistry/genetics/metabolism/*physiology ; Binding Sites ; DNA Mutational Analysis ; *Models, Molecular ; Plants, Genetically Modified ; Protein Binding ; Protein Structure, Tertiary ; Signal Transduction/*physiology
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  • 8
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    Chaperone-mediated pathway of proteasome regulatory particle assembly (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-05
    Description: The proteasome is a protease that controls diverse processes in eukaryotic cells. Its regulatory particle (RP) initiates the degradation of ubiquitin-protein conjugates by unfolding the substrate and translocating it into the proteasome core particle (CP) to be degraded. The RP has 19 subunits, and their pathway of assembly is not understood. Here we show that in the yeast Saccharomyces cerevisiae three proteins are found associated with RP but not with the RP-CP holoenzyme: Nas6, Rpn14 and Hsm3. Mutations in the corresponding genes confer proteasome loss-of-function phenotypes, despite their virtual absence from the holoenzyme. These effects result from deficient RP assembly. Thus, Nas6, Rpn14 and Hsm3 are RP chaperones. The RP contains six ATPases-the Rpt proteins-and each RP chaperone binds to the carboxy-terminal domain of a specific Rpt. We show in an accompanying study that RP assembly is templated through the Rpt C termini, apparently by their insertion into binding pockets in the CP. Thus, RP chaperones may regulate proteasome assembly by directly restricting the accessibility of Rpt C termini to the CP. In addition, competition between the RP chaperones and the CP for Rpt engagement may explain the release of RP chaperones as proteasomes mature.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727592/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727592/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roelofs, Jeroen -- Park, Soyeon -- Haas, Wilhelm -- Tian, Geng -- McAllister, Fiona E -- Huo, Ying -- Lee, Byung-Hoon -- Zhang, Fan -- Shi, Yigong -- Gygi, Steven P -- Finley, Daniel -- 5F32GM75737-2/GM/NIGMS NIH HHS/ -- GM043601/GM/NIGMS NIH HHS/ -- GM67945/GM/NIGMS NIH HHS/ -- R37 GM043601/GM/NIGMS NIH HHS/ -- R37 GM043601-19/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):861-5. doi: 10.1038/nature08063.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Carrier Proteins/genetics/metabolism ; Conserved Sequence ; Evolution, Molecular ; Holoenzymes/chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Chaperones/genetics/*metabolism ; Mutation ; Phenotype ; Proteasome Endopeptidase Complex/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism
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  • 9
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    Structural basis of abscisic acid signalling (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-27
    Description: The phytohormone abscisic acid (ABA) mediates the adaptation of plants to environmental stresses such as drought and regulates developmental signals such as seed maturation. Within plants, the PYR/PYL/RCAR family of START proteins receives ABA to inhibit the phosphatase activity of the group-A protein phosphatases 2C (PP2Cs), which are major negative regulators in ABA signalling. Here we present the crystal structures of the ABA receptor PYL1 bound with (+)-ABA, and the complex formed by the further binding of (+)-ABA-bound PYL1 with the PP2C protein ABI1. PYL1 binds (+)-ABA using the START-protein-specific ligand-binding site, thereby forming a hydrophobic pocket on the surface of the closed lid. (+)-ABA-bound PYL1 tightly interacts with a PP2C domain of ABI1 by using the hydrophobic pocket to cover the active site of ABI1 like a plug. Our results reveal the structural basis of the mechanism of (+)-ABA-dependent inhibition of ABI1 by PYL1 in ABA signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miyazono, Ken-Ichi -- Miyakawa, Takuya -- Sawano, Yoriko -- Kubota, Keiko -- Kang, Hee-Jin -- Asano, Atsuko -- Miyauchi, Yumiko -- Takahashi, Mihoko -- Zhi, Yuehua -- Fujita, Yasunari -- Yoshida, Takuya -- Kodaira, Ken-Suke -- Yamaguchi-Shinozaki, Kazuko -- Tanokura, Masaru -- England -- Nature. 2009 Dec 3;462(7273):609-14. doi: 10.1038/nature08583.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19855379" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*physiology ; Arabidopsis/*physiology ; Arabidopsis Proteins/*chemistry/*metabolism ; Binding Sites ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/metabolism ; *Signal Transduction
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  • 10
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    Direct inhibition of the NOTCH transcription factor complex (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-13
    Description: Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951323/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moellering, Raymond E -- Cornejo, Melanie -- Davis, Tina N -- Del Bianco, Cristina -- Aster, Jon C -- Blacklow, Stephen C -- Kung, Andrew L -- Gilliland, D Gary -- Verdine, Gregory L -- Bradner, James E -- 5T32GM007598/GM/NIGMS NIH HHS/ -- N01-CO-12400/CO/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P01 CA119070-049001/CA/NCI NIH HHS/ -- R01 CA092433/CA/NCI NIH HHS/ -- R01 CA092433-06A2/CA/NCI NIH HHS/ -- R56 CA092433/CA/NCI NIH HHS/ -- R56 CA092433-06A1/CA/NCI NIH HHS/ -- T32 GM007598/GM/NIGMS NIH HHS/ -- T32 GM007598-30/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):182-8. doi: 10.1038/nature08543.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907488" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding, Competitive ; Cell Line, Tumor ; Cell Membrane Permeability ; Cell Proliferation/drug effects ; DNA-Binding Proteins/chemistry/metabolism ; Disease Models, Animal ; Drosophila Proteins/chemistry ; Gene Expression Regulation, Neoplastic/drug effects ; Genome/drug effects/genetics ; Humans ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/chemistry ; Peptides/chemical synthesis/chemistry/metabolism/*pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/pathology ; Protein Binding/drug effects ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptor, Notch1/*antagonists & inhibitors/chemistry/metabolism ; Signal Transduction/drug effects ; Substrate Specificity ; Transcription Factors/chemistry/metabolism ; Transcriptional Activation/*drug effects
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    Cooperative binding of two acetylation marks on a histone tail by a single bromodomain (2009)
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    Publication Date: 2009-10-02
    Description: A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family. Whereas effector-mediated recognition of single post-translational modifications is well characterized, how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules. For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark. Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family. Brdt associates with hyperacetylated histone H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm. Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo. Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moriniere, Jeanne -- Rousseaux, Sophie -- Steuerwald, Ulrich -- Soler-Lopez, Montserrat -- Curtet, Sandrine -- Vitte, Anne-Laure -- Govin, Jerome -- Gaucher, Jonathan -- Sadoul, Karin -- Hart, Darren J -- Krijgsveld, Jeroen -- Khochbin, Saadi -- Muller, Christoph W -- Petosa, Carlo -- England -- Nature. 2009 Oct 1;461(7264):664-8. doi: 10.1038/nature08397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, BP 181, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794495" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Allosteric Regulation ; Animals ; Binding Sites ; COS Cells ; Cercopithecus aethiops ; Chromatin/chemistry/metabolism ; Crystallography, X-Ray ; Histones/*chemistry/*metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Substrate Specificity
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    The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism (2009)
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    Publication Date: 2009-05-08
    Description: Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore. They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system. PFTs can be subdivided into two classes, alpha-PFTs and beta-PFTs, depending on the suspected mode of membrane integration, either by alpha-helical or beta-sheet elements. The only high-resolution structure of a transmembrane PFT pore is available for a beta-PFT--alpha-haemolysin from Staphylococcus aureus. Cytolysin A (ClyA, also known as HlyE), an alpha-PFT, is a cytolytic -helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains. ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion. Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA must undergo large conformational changes to form the transmembrane pore. Here we report the 3.3 A crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 A, of parts of the monomer, reorganization of the hydrophobic core, and transitions of -sheets and loop regions to -helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mueller, Marcus -- Grauschopf, Ulla -- Maier, Timm -- Glockshuber, Rudi -- Ban, Nenad -- England -- Nature. 2009 Jun 4;459(7247):726-30. doi: 10.1038/nature08026.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19421192" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry ; Crystallography, X-Ray ; Escherichia coli K12/*chemistry ; Escherichia coli Proteins/*chemistry ; Hemolysin Proteins/*chemistry ; Membrane Proteins/*chemistry ; *Models, Molecular ; *Protein Folding ; Protein Structure, Tertiary
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    Structure and hydration of membranes embedded with voltage-sensing domains (2009)
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    Publication Date: 2009-11-27
    Description: Despite the growing number of atomic-resolution membrane protein structures, direct structural information about proteins in their native membrane environment is scarce. This problem is particularly relevant in the case of the highly charged S1-S4 voltage-sensing domains responsible for nerve impulses, where interactions with the lipid bilayer are critical for the function of voltage-activated ion channels. Here we use neutron diffraction, solid-state nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations to investigate the structure and hydration of bilayer membranes containing S1-S4 voltage-sensing domains. Our results show that voltage sensors adopt transmembrane orientations and cause a modest reshaping of the surrounding lipid bilayer, and that water molecules intimately interact with the protein within the membrane. These structural findings indicate that voltage sensors have evolved to interact with the lipid membrane while keeping energetic and structural perturbations to a minimum, and that water penetrates the membrane, to hydrate charged residues and shape the transmembrane electric field.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784928/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784928/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krepkiy, Dmitriy -- Mihailescu, Mihaela -- Freites, J Alfredo -- Schow, Eric V -- Worcester, David L -- Gawrisch, Klaus -- Tobias, Douglas J -- White, Stephen H -- Swartz, Kenton J -- GM74737/GM/NIGMS NIH HHS/ -- GM86685/GM/NIGMS NIH HHS/ -- P01 GM086685/GM/NIGMS NIH HHS/ -- R01 GM074637/GM/NIGMS NIH HHS/ -- R01 RR014812/RR/NCRR NIH HHS/ -- ZIA NS002945-13/Intramural NIH HHS/ -- England -- Nature. 2009 Nov 26;462(7272):473-9. doi: 10.1038/nature08542.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940918" target="_blank"〉PubMed〈/a〉
    Keywords: Archaeal Proteins/chemistry/metabolism ; Circular Dichroism ; Lipid Bilayers/*chemistry/*metabolism ; Membrane Lipids/analysis/chemistry/metabolism ; *Membrane Potentials ; Models, Molecular ; Molecular Dynamics Simulation ; Neutron Diffraction ; Nuclear Magnetic Resonance, Biomolecular ; Potassium Channels, Voltage-Gated/*chemistry/metabolism ; Protein Structure, Tertiary ; Spectrometry, Fluorescence ; Water/*analysis/metabolism
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    Detection and trapping of intermediate states priming nicotinic receptor channel opening (2009)
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    Publication Date: 2009-04-03
    Description: In the course of synaptic transmission in the brain and periphery, acetylcholine receptors (AChRs) rapidly transduce a chemical signal into an electrical impulse. The speed of transduction is facilitated by rapid ACh association and dissociation, suggesting a binding site relatively non-selective for small cations. Selective transduction has been thought to originate from the ability of ACh, over that of other organic cations, to trigger the subsequent channel-opening step. However, transitions to and from the open state were shown to be similar for agonists with widely different efficacies. By studying mutant AChRs, we show here that the ultimate closed-to-open transition is agonist-independent and preceded by two primed closed states; the first primed state elicits brief openings, whereas the second elicits long-lived openings. Long-lived openings and the associated primed state are detected in the absence and presence of an agonist, and exhibit the same kinetic signatures under both conditions. By covalently locking the agonist-binding sites in the bound conformation, we find that each site initiates a priming step. Thus, a change in binding-site conformation primes the AChR for channel opening in a process that enables selective activation by ACh while maximizing the speed and efficiency of the biological response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712348/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712348/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mukhtasimova, Nuriya -- Lee, Won Yong -- Wang, Hai-Long -- Sine, Steven M -- NS031744/NS/NINDS NIH HHS/ -- R01 NS031744/NS/NINDS NIH HHS/ -- R01 NS031744-18/NS/NINDS NIH HHS/ -- England -- Nature. 2009 May 21;459(7245):451-4. doi: 10.1038/nature07923. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339970" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Disulfides/metabolism ; Electric Conductivity ; Humans ; Kinetics ; Models, Molecular ; *Movement ; Nicotinic Agonists/pharmacology ; Patch-Clamp Techniques ; Protein Structure, Tertiary ; Receptors, Nicotinic/*chemistry/genetics/*metabolism ; Synaptic Transmission/physiology ; Torpedo
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    New protein structures replace the old (2009)
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    Publication Date: 2009-06-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanderson, Katharine -- England -- Nature. 2009 Jun 25;459(7250):1038-9. doi: 10.1038/4591038b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19553956" target="_blank"〉PubMed〈/a〉
    Keywords: Databases, Protein/*standards/trends ; Humans ; *Models, Molecular ; Netherlands ; Protein Structure, Tertiary ; Software/standards
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    The abscisic acid receptor PYR1 in complex with abscisic acid (2009)
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    Publication Date: 2009-11-10
    Description: The plant hormone abscisic acid (ABA) has a central role in coordinating the adaptive response in situations of decreased water availability as well as the regulation of plant growth and development. Recently, a 14-member family of intracellular ABA receptors, named PYR/PYL/RCAR, has been identified. These proteins inhibit in an ABA-dependent manner the activity of a family of key negative regulators of the ABA signalling pathway: the group-A protein phosphatases type 2C (PP2Cs). Here we present the crystal structure of Arabidopsis thaliana PYR1, which consists of a dimer in which one of the subunits is bound to ABA. In the ligand-bound subunit, the loops surrounding the entry to the binding cavity fold over the ABA molecule, enclosing it inside, whereas in the empty subunit they form a channel leaving an open access to the cavity, indicating that conformational changes in these loops have a critical role in the stabilization of the hormone-receptor complex. By providing structural details on the ABA-binding pocket, this work paves the way for the development of new small molecules able to activate the plant stress response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santiago, Julia -- Dupeux, Florine -- Round, Adam -- Antoni, Regina -- Park, Sang-Youl -- Jamin, Marc -- Cutler, Sean R -- Rodriguez, Pedro Luis -- Marquez, Jose Antonio -- England -- Nature. 2009 Dec 3;462(7273):665-8. doi: 10.1038/nature08591. Epub 2009 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Biologia Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientificas-Universidad Politecnica de Valencia, ES-46022 Valencia, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898494" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Arabidopsis ; Arabidopsis Proteins/*chemistry/*metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary
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    Dynamic activation of an allosteric regulatory protein (2009)
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    Publication Date: 2009-11-20
    Description: Allosteric regulation is used as a very efficient mechanism to control protein activity in most biological processes, including signal transduction, metabolism, catalysis and gene regulation. Allosteric proteins can exist in several conformational states with distinct binding or enzymatic activity. Effectors are considered to function in a purely structural manner by selectively stabilizing a specific conformational state, thereby regulating protein activity. Here we show that allosteric proteins can be regulated predominantly by changes in their structural dynamics. We have used NMR spectroscopy and isothermal titration calorimetry to characterize cyclic AMP (cAMP) binding to the catabolite activator protein (CAP), a transcriptional activator that has been a prototype for understanding effector-mediated allosteric control of protein activity. cAMP switches CAP from the 'off' state (inactive), which binds DNA weakly and non-specifically, to the 'on' state (active), which binds DNA strongly and specifically. In contrast, cAMP binding to a single CAP mutant, CAP-S62F, fails to elicit the active conformation; yet, cAMP binding to CAP-S62F strongly activates the protein for DNA binding. NMR and thermodynamic analyses show that despite the fact that CAP-S62F-cAMP(2) adopts the inactive conformation, its strong binding to DNA is driven by a large conformational entropy originating in enhanced protein motions induced by DNA binding. The results provide strong evidence that changes in protein motions may activate allosteric proteins that are otherwise structurally inactive.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tzeng, Shiou-Ru -- Kalodimos, Charalampos G -- England -- Nature. 2009 Nov 19;462(7271):368-72. doi: 10.1038/nature08560.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924217" target="_blank"〉PubMed〈/a〉
    Keywords: Cyclic AMP/chemistry/metabolism ; Cyclic AMP Receptor Protein/chemistry/*metabolism ; DNA/metabolism ; *Energy Metabolism ; Escherichia coli/*metabolism ; Escherichia coli Proteins/chemistry/*metabolism ; Models, Molecular ; Protein Binding ; Protein Structure, Tertiary
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    ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor (2009)
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    Publication Date: 2009-09-01
    Description: The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762480/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alvarado, Diego -- Klein, Daryl E -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-09/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- R01 CA125432-02/CA/NCI NIH HHS/ -- R01 CA125432-03/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):287-91. doi: 10.1038/nature08297. Epub 2009 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19718021" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Drosophila melanogaster/chemistry/*metabolism ; Enzyme Activation ; Humans ; Ligands ; Models, Molecular ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Receptor, ErbB-2/antagonists & inhibitors/*chemistry/*metabolism ; Receptors, Invertebrate Peptide/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Scattering, Small Angle ; Solubility ; X-Ray Diffraction
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    Structural biology: Highly charged meetings (2009)
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    Publication Date: 2009-11-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Anthony G -- England -- Nature. 2009 Nov 26;462(7272):420-1. doi: 10.1038/462420a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940907" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/*chemistry/*metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Neutron Diffraction ; Potassium Channels, Voltage-Gated/*chemistry/*metabolism ; Protein Structure, Tertiary ; Static Electricity
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    Structural insight into the autoinhibition mechanism of AMP-activated protein kinase (2009)
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    Publication Date: 2009-05-29
    Description: The AMP-activated protein kinase (AMPK) is characterized by its ability to bind to AMP, which enables it to adjust enzymatic activity by sensing the cellular energy status and maintain the balance between ATP production and consumption in eukaryotic cells. It also has important roles in the regulation of cell growth and proliferation, and in the establishment and maintenance of cell polarity. These important functions have rendered AMPK an important drug target for obesity, type 2 diabetes and cancer treatments. However, the regulatory mechanism of AMPK activity by AMP binding remains unsolved. Here we report the crystal structures of an unphosphorylated fragment of the AMPK alpha-subunit (KD-AID) from Schizosaccharomyces pombe that contains both the catalytic kinase domain and an autoinhibitory domain (AID), and of a phosphorylated kinase domain from Saccharomyces cerevisiae (Snf1-pKD). The AID binds, from the 'backside', to the hinge region of its kinase domain, forming contacts with both amino-terminal and carboxy-terminal lobes. Structural analyses indicate that AID binding might constrain the mobility of helix alphaC, hence resulting in an autoinhibited KD-AID with much lower kinase activity than that of the kinase domain alone. AMP activates AMPK both allosterically and by inhibiting dephosphorylation. Further in vitro kinetic studies demonstrate that disruption of the KD-AID interface reverses the autoinhibition and these AMPK heterotrimeric mutants no longer respond to the change in AMP concentration. The structural and biochemical data have shown the primary mechanism of AMPK autoinhibition and suggest a conformational switch model for AMPK activation by AMP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lei -- Jiao, Zhi-Hao -- Zheng, Li-Sha -- Zhang, Yuan-Yuan -- Xie, Shu-Tao -- Wang, Zhi-Xin -- Wu, Jia-Wei -- England -- Nature. 2009 Jun 25;459(7250):1146-9. doi: 10.1038/nature08075. Epub 2009 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19474788" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*chemistry/*metabolism ; Adenosine Monophosphate/metabolism ; Amino Acid Sequence ; Animals ; *Models, Molecular ; Molecular Sequence Data ; Mutation ; Phosphorylation ; Protein Structure, Tertiary ; Rats ; Saccharomyces cerevisiae/*enzymology ; Schizosaccharomyces/*enzymology ; Sequence Alignment
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    The origin of the electrostatic perturbation in acetoacetate decarboxylase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-22
    Description: Acetoacetate decarboxylase (AADase) has long been cited as the prototypical example of the marked shifts in the pK(a) values of ionizable groups that can occur in an enzyme active site. In 1966, it was hypothesized that in AADase the origin of the large pK(a) perturbation (-4.5 log units) observed in the nucleophilic Lys 115 results from the proximity of Lys 116, marking the first proposal of microenvironment effects in enzymology. The electrostatic perturbation hypothesis has been demonstrated in a number of enzymes, but never for the enzyme that inspired its conception, owing to the lack of a three-dimensional structure. Here we present the X-ray crystal structures of AADase and of the enamine adduct with the substrate analogue 2,4-pentanedione. Surprisingly, the shift of the pK(a) of Lys 115 is not due to the proximity of Lys 116, the side chain of which is oriented away from the active site. Instead, Lys 116 participates in the structural anchoring of Lys 115 in a long, hydrophobic funnel provided by the novel fold of the enzyme. Thus, AADase perturbs the pK(a) of the nucleophile by means of a desolvation effect by placement of the side chain into the protein core while enforcing the proximity of polar residues, which facilitate decarboxylation through electrostatic and steric effects.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ho, Meng-Chiao -- Menetret, Jean-Francois -- Tsuruta, Hiro -- Allen, Karen N -- England -- Nature. 2009 May 21;459(7245):393-7. doi: 10.1038/nature07938.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458715" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Carboxy-Lyases/*chemistry ; Catalytic Domain ; Chromobacterium/*enzymology ; Clostridium acetobutylicum/*enzymology ; Crystallography, X-Ray ; Decarboxylation ; Hydrophobic and Hydrophilic Interactions ; Lysine/chemistry/metabolism ; Models, Molecular ; Pentanones/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Static Electricity
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    Hidden alternative structures of proline isomerase essential for catalysis (2009)
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    Publication Date: 2009-12-04
    Description: A long-standing challenge is to understand at the atomic level how protein dynamics contribute to enzyme catalysis. X-ray crystallography can provide snapshots of conformational substates sampled during enzymatic reactions, while NMR relaxation methods reveal the rates of interconversion between substates and the corresponding relative populations. However, these current methods cannot simultaneously reveal the detailed atomic structures of the rare states and rationalize the finding that intrinsic motions in the free enzyme occur on a timescale similar to the catalytic turnover rate. Here we introduce dual strategies of ambient-temperature X-ray crystallographic data collection and automated electron-density sampling to structurally unravel interconverting substates of the human proline isomerase, cyclophilin A (CYPA, also known as PPIA). A conservative mutation outside the active site was designed to stabilize features of the previously hidden minor conformation. This mutation not only inverts the equilibrium between the substates, but also causes large, parallel reductions in the conformational interconversion rates and the catalytic rate. These studies introduce crystallographic approaches to define functional minor protein conformations and, in combination with NMR analysis of the enzyme dynamics in solution, show how collective motions directly contribute to the catalytic power of an enzyme.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805857/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fraser, James S -- Clarkson, Michael W -- Degnan, Sheena C -- Erion, Renske -- Kern, Dorothee -- Alber, Tom -- R01 GM048958/GM/NIGMS NIH HHS/ -- R01 GM048958-16/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 3;462(7273):669-73. doi: 10.1038/nature08615.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology/QB3, University of California, Berkeley, California 94720-3220, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19956261" target="_blank"〉PubMed〈/a〉
    Keywords: Catalysis ; Crystallography, X-Ray/*methods ; Cyclophilin A/*chemistry/genetics ; Humans ; *Models, Molecular ; Mutation ; Protein Structure, Tertiary ; Temperature
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    Structure and mechanism of a bacterial light-regulated cyclic nucleotide phosphodiesterase (2009)
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    Publication Date: 2009-06-19
    Description: The ability to respond to light is crucial for most organisms. BLUF is a recently identified photoreceptor protein domain that senses blue light using a FAD chromophore. BLUF domains are present in various proteins from the Bacteria, Euglenozoa and Fungi. Although structures of single-domain BLUF proteins have been determined, none are available for a BLUF protein containing a functional output domain; the mechanism of light activation in this new class of photoreceptors has thus remained poorly understood. Here we report the biochemical, structural and mechanistic characterization of a full-length, active photoreceptor, BlrP1 (also known as KPN_01598), from Klebsiella pneumoniae. BlrP1 consists of a BLUF sensor domain and a phosphodiesterase EAL output domain which hydrolyses cyclic dimeric GMP (c-di-GMP). This ubiquitous second messenger controls motility, biofilm formation, virulence and antibiotic resistance in the Bacteria. Crystal structures of BlrP1 complexed with its substrate and metal ions involved in catalysis or in enzyme inhibition provide a detailed understanding of the mechanism of the EAL-domain c-di-GMP phosphodiesterases. These structures also sketch out a path of light activation of the phosphodiesterase output activity. Photon absorption by the BLUF domain of one subunit of the antiparallel BlrP1 homodimer activates the EAL domain of the second subunit through allosteric communication transmitted through conserved domain-domain interfaces.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barends, Thomas R M -- Hartmann, Elisabeth -- Griese, Julia J -- Beitlich, Thorsten -- Kirienko, Natalia V -- Ryjenkov, Dmitri A -- Reinstein, Jochen -- Shoeman, Robert L -- Gomelsky, Mark -- Schlichting, Ilme -- England -- Nature. 2009 Jun 18;459(7249):1015-8. doi: 10.1038/nature07966.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Medical Research, Department of Biomolecular Mechanisms, Jahnstrasse 29, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536266" target="_blank"〉PubMed〈/a〉
    Keywords: 3',5'-Cyclic-GMP Phosphodiesterases/*chemistry/metabolism/*radiation effects ; Allosteric Regulation/radiation effects ; Biocatalysis/radiation effects ; Catalytic Domain ; Crystallography, X-Ray ; Cyclic GMP/analogs & derivatives/metabolism ; Klebsiella pneumoniae/*enzymology ; *Light ; Metals/metabolism ; Models, Molecular ; Phosphorus/metabolism ; Photons ; Photoreceptors, Microbial/*chemistry/metabolism/*radiation effects ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary
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    Coordinating DNA replication by means of priming loop and differential synthesis rate (2009)
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    Publication Date: 2009-11-20
    Description: Genomic DNA is replicated by two DNA polymerase molecules, one of which works in close association with the helicase to copy the leading-strand template in a continuous manner while the second copies the already unwound lagging-strand template in a discontinuous manner through the synthesis of Okazaki fragments. Considering that the lagging-strand polymerase has to recycle after the completion of every Okazaki fragment through the slow steps of primer synthesis and hand-off to the polymerase, it is not understood how the two strands are synthesized with the same net rate. Here we show, using the T7 replication proteins, that RNA primers are made 'on the fly' during ongoing DNA synthesis and that the leading-strand T7 replisome does not pause during primer synthesis, contrary to previous reports. Instead, the leading-strand polymerase remains limited by the speed of the helicase; it therefore synthesizes DNA more slowly than the lagging-strand polymerase. We show that the primase-helicase T7 gp4 maintains contact with the priming sequence during ongoing DNA synthesis; the nascent lagging-strand template therefore organizes into a priming loop that keeps the primer in physical proximity to the replication complex. Our findings provide three synergistic mechanisms of coordination: first, primers are made concomitantly with DNA synthesis; second, the priming loop ensures efficient primer use and hand-off to the polymerase; and third, the lagging-strand polymerase copies DNA faster, which allows it to keep up with leading-strand DNA synthesis overall.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896039/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pandey, Manjula -- Syed, Salman -- Donmez, Ilker -- Patel, Gayatri -- Ha, Taekjip -- Patel, Smita S -- GM065367/GM/NIGMS NIH HHS/ -- GM55310/GM/NIGMS NIH HHS/ -- R01 GM055310/GM/NIGMS NIH HHS/ -- R01 GM055310-14/GM/NIGMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 17;462(7275):940-3. doi: 10.1038/nature08611. Epub 2009 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924126" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage T7/*enzymology/genetics/*physiology ; DNA Primase/chemistry/metabolism ; DNA Replication/*physiology ; DNA, Viral/biosynthesis/metabolism ; DNA-Directed DNA Polymerase/chemistry/metabolism ; Fluorescence Resonance Energy Transfer ; Kinetics ; Models, Biological ; Multienzyme Complexes/chemistry/metabolism ; Protein Structure, Tertiary ; RNA/biosynthesis ; Time Factors
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    Macrophage elastase kills bacteria within murine macrophages (2009)
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    Publication Date: 2009-06-19
    Description: Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that macrophage-derived proteinases may contribute to the antimicrobial properties of macrophages. Macrophage elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12(-/-) mice exhibit impaired bacterial clearance and increased mortality when challenged with both gram-negative and gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed beta loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885871/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Houghton, A McGarry -- Hartzell, William O -- Robbins, Clinton S -- Gomis-Ruth, F Xavier -- Shapiro, Steven D -- R01 HL082541/HL/NHLBI NIH HHS/ -- R01 HL082541-01/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Jul 30;460(7255):637-41. doi: 10.1038/nature08181. Epub 2009 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. houghtonm@dom.pitt.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536155" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Anti-Bacterial Agents/pharmacology ; Bacterial Infections/*enzymology ; *Bacterial Physiological Phenomena ; Humans ; Kaplan-Meier Estimate ; Klebsiella pneumoniae/drug effects ; Macrophages/*enzymology/*microbiology ; Matrix Metalloproteinase 12/chemistry/genetics/*metabolism/pharmacology ; Mice ; Mice, Knockout ; Models, Molecular ; Molecular Sequence Data ; Protein Structure, Tertiary ; Staphylococcus aureus/drug effects
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    GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis (2009)
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    Publication Date: 2009-04-21
    Description: The post-translational modifications of histone tails generate a 'histone code' that defines local and global chromatin states. The resultant regulation of gene function is thought to govern cell fate, proliferation and differentiation. Reversible histone modifications such as methylation are under mutual controls to organize chromosomal events. Among the histone modifications, methylation of specific lysine and arginine residues seems to be critical for chromatin configuration and control of gene expression. Methylation of histone H3 lysine 4 (H3K4) changes chromatin into a transcriptionally active state. Reversible modification of proteins by beta-N-acetylglucosamine (O-GlcNAc) in response to serum glucose levels regulates diverse cellular processes. However, the epigenetic impact of protein GlcNAcylation is unknown. Here we report that nuclear GlcNAcylation of a histone lysine methyltransferase (HKMT), MLL5, by O-GlcNAc transferase facilitates retinoic-acid-induced granulopoiesis in human HL60 promyelocytes through methylation of H3K4. MLL5 is biochemically identified in a GlcNAcylation-dependent multi-subunit complex associating with nuclear retinoic acid receptor RARalpha (also known as RARA), serving as a mono- and di-methyl transferase to H3K4. GlcNAcylation at Thr 440 in the MLL5 SET domain evokes its H3K4 HKMT activity and co-activates RARalpha in target gene promoters. Increased nuclear GlcNAcylation by means of O-GlcNAc transferase potentiates retinoic-acid-induced HL60 granulopoiesis and restores the retinoic acid response in the retinoic-acid-resistant HL60-R2 cell line. Thus, nuclear MLL5 GlcNAcylation triggers cell lineage determination of HL60 through activation of its HKMT activity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fujiki, Ryoji -- Chikanishi, Toshihiro -- Hashiba, Waka -- Ito, Hiroaki -- Takada, Ichiro -- Roeder, Robert G -- Kitagawa, Hirochika -- Kato, Shigeaki -- England -- Nature. 2009 May 21;459(7245):455-9. doi: 10.1038/nature07954. Epub 2009 Apr 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19377461" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/*metabolism ; Cell Lineage ; Cell Nucleus/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Granulocytes/*cytology/*drug effects ; HL-60 Cells ; Histone-Lysine N-Methyltransferase/chemistry/*metabolism ; Humans ; Leukopoiesis/*drug effects ; Multiprotein Complexes/chemistry/isolation & purification/metabolism ; N-Acetylglucosaminyltransferases/chemistry/*metabolism ; Protein Structure, Tertiary ; Receptors, Retinoic Acid/metabolism ; Threonine/metabolism ; Tretinoin/*pharmacology
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    Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks (2009)
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    Publication Date: 2009-12-18
    Description: DNA double-strand breaks (DSBs) are highly cytotoxic lesions that are generated by ionizing radiation and various DNA-damaging chemicals. Following DSB formation, cells activate the DNA-damage response (DDR) protein kinases ATM, ATR and DNA-PK (also known as PRKDC). These then trigger histone H2AX (also known as H2AFX) phosphorylation and the accumulation of proteins such as MDC1, 53BP1 (also known as TP53BP1), BRCA1, CtIP (also known as RBBP8), RNF8 and RNF168/RIDDLIN into ionizing radiation-induced foci (IRIF) that amplify DSB signalling and promote DSB repair. Attachment of small ubiquitin-related modifier (SUMO) to target proteins controls diverse cellular functions. Here, we show that SUMO1, SUMO2 and SUMO3 accumulate at DSB sites in mammalian cells, with SUMO1 and SUMO2/3 accrual requiring the E3 ligase enzymes PIAS4 and PIAS1. We also establish that PIAS1 and PIAS4 are recruited to damage sites via mechanisms requiring their SAP domains, and are needed for the productive association of 53BP1, BRCA1 and RNF168 with such regions. Furthermore, we show that PIAS1 and PIAS4 promote DSB repair and confer ionizing radiation resistance. Finally, we establish that PIAS1 and PIAS4 are required for effective ubiquitin-adduct formation mediated by RNF8, RNF168 and BRCA1 at sites of DNA damage. These findings thus identify PIAS1 and PIAS4 as components of the DDR and reveal how protein recruitment to DSB sites is controlled by coordinated SUMOylation and ubiquitylation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904806/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galanty, Yaron -- Belotserkovskaya, Rimma -- Coates, Julia -- Polo, Sophie -- Miller, Kyle M -- Jackson, Stephen P -- 086861/Wellcome Trust/United Kingdom -- 11224/Cancer Research UK/United Kingdom -- A5290/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Dec 17;462(7275):935-9. doi: 10.1038/nature08657.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20016603" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; BRCA1 Protein/metabolism ; Cell Line ; Cell Line, Tumor ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/genetics/metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Models, Biological ; Phosphorylation ; Protein Inhibitors of Activated STAT/chemistry/genetics/*metabolism ; Protein Structure, Tertiary ; Replication Protein A/metabolism ; Small Ubiquitin-Related Modifier Proteins/genetics/*metabolism ; Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
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    Structural insights into mechanisms of the small RNA methyltransferase HEN1 (2009)
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    Publication Date: 2009-10-09
    Description: RNA silencing is a conserved regulatory mechanism in fungi, plants and animals that regulates gene expression and defence against viruses and transgenes. Small silencing RNAs of approximately 20-30 nucleotides and their associated effector proteins, the Argonaute family proteins, are the central components in RNA silencing. A subset of small RNAs, such as microRNAs and small interfering RNAs (siRNAs) in plants, Piwi-interacting RNAs in animals and siRNAs in Drosophila, requires an additional crucial step for their maturation; that is, 2'-O-methylation on the 3' terminal nucleotide. A conserved S-adenosyl-l-methionine-dependent RNA methyltransferase, HUA ENHANCER 1 (HEN1), and its homologues are responsible for this specific modification. Here we report the 3.1 A crystal structure of full-length HEN1 from Arabidopsis in complex with a 22-nucleotide small RNA duplex and cofactor product S-adenosyl-l-homocysteine. Highly cooperative recognition of the small RNA substrate by multiple RNA binding domains and the methyltransferase domain in HEN1 measures the length of the RNA duplex and determines the substrate specificity. Metal ion coordination by both 2' and 3' hydroxyls on the 3'-terminal nucleotide and four invariant residues in the active site of the methyltransferase domain suggests a novel Mg(2+)-dependent 2'-O-methylation mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Ying -- Ji, Lijuan -- Huang, Qichen -- Vassylyev, Dmitry G -- Chen, Xuemei -- Ma, Jin-Biao -- GM074252/GM/NIGMS NIH HHS/ -- R01 GM074840/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Oct 8;461(7265):823-7. doi: 10.1038/nature08433.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812675" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Arabidopsis/*enzymology/genetics ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Magnesium/metabolism ; Methylation ; Methyltransferases/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Protein Structure, Tertiary ; RNA/genetics/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; S-Adenosylhomocysteine/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Biochemistry: Enzyme's black box cracked open (2009)
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    Publication Date: 2009-10-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sherman, David H -- England -- Nature. 2009 Oct 22;461(7267):1068-9. doi: 10.1038/4611068a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847256" target="_blank"〉PubMed〈/a〉
    Keywords: Aflatoxin B1/biosynthesis ; Aspergillus/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Cyclization ; Pantetheine/analogs & derivatives/metabolism ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structure of the BK potassium channel in a lipid membrane from electron cryomicroscopy (2009)
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    Publication Date: 2009-09-01
    Description: A long-sought goal in structural biology has been the imaging of membrane proteins in their membrane environments. This goal has been achieved with electron crystallography in those special cases where a protein forms highly ordered arrays in lipid bilayers. It has also been achieved by NMR methods in proteins up to 50 kilodaltons (kDa) in size, although milligram quantities of protein and isotopic labelling are required. For structural analysis of large soluble proteins in microgram quantities, an increasingly powerful method that does not require crystallization is single-particle reconstruction from electron microscopy of cryogenically cooled samples (electron cryomicroscopy (cryo-EM)). Here we report the first single-particle cryo-EM study of a membrane protein, the human large-conductance calcium- and voltage-activated potassium channel (BK), in a lipid environment. The new method is called random spherically constrained (RSC) single-particle reconstruction. BK channels, members of the six-transmembrane-segment (6TM) ion channel family, were reconstituted at low density into lipid vesicles (liposomes), and their function was verified by a potassium flux assay. Vesicles were also frozen in vitreous ice and imaged in an electron microscope. From images of 8,400 individual protein particles, a three-dimensional (3D) reconstruction of the BK channel and its membrane environment was obtained at a resolution of 1.7-2.0 nm. Not requiring the formation of crystals, the RSC approach promises to be useful in the structural study of many other membrane proteins as well.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797367/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797367/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Liguo -- Sigworth, Fred J -- P01 GM062580/GM/NIGMS NIH HHS/ -- P01 GM062580-06A10007/GM/NIGMS NIH HHS/ -- P01 GM062580-070007/GM/NIGMS NIH HHS/ -- P01 GM062580-080007/GM/NIGMS NIH HHS/ -- R01 NS021501/NS/NINDS NIH HHS/ -- R01 NS021501-19/NS/NINDS NIH HHS/ -- R01 NS021501-19S1/NS/NINDS NIH HHS/ -- R01 NS021501-20/NS/NINDS NIH HHS/ -- R01 NS021501-21/NS/NINDS NIH HHS/ -- R01 NS021501-22/NS/NINDS NIH HHS/ -- R01 NS021501-23/NS/NINDS NIH HHS/ -- R01 NS021501-24/NS/NINDS NIH HHS/ -- S10 RR014739/RR/NCRR NIH HHS/ -- S10 RR014739-01/RR/NCRR NIH HHS/ -- S10 RR014739-018020/RR/NCRR NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):292-5. doi: 10.1038/nature08291. Epub 2009 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Physiology, Yale University, 333 Cedar Street, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19718020" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Cryoelectron Microscopy/*methods ; Humans ; Ion Channel Gating ; Large-Conductance Calcium-Activated Potassium Channel alpha ; Subunits/*chemistry/genetics/metabolism/*ultrastructure ; Liposomes/chemistry/*metabolism ; Membrane Lipids/*metabolism ; Membrane Potentials ; Models, Molecular ; Potassium/metabolism ; Protein Structure, Tertiary ; Proteolipids/chemistry/metabolism ; Substrate Specificity
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    Structural biology: Trimeric ion-channel design (2009)
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    Publication Date: 2009-07-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silberberg, Shai D -- Swartz, Kenton J -- ZIA NS003018-03/Intramural NIH HHS/ -- England -- Nature. 2009 Jul 30;460(7255):580-1. doi: 10.1038/460580a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641581" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Ion Channels/*chemistry ; Membrane Proteins/*chemistry ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Purinergic P2/*chemistry
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    Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization (2009)
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    Publication Date: 2009-10-23
    Description: Polyketides are a class of natural products with diverse structures and biological activities. The structural variability of aromatic products of fungal nonreducing, multidomain iterative polyketide synthases (NR-PKS group of IPKSs) results from regiospecific cyclizations of reactive poly-beta-keto intermediates. How poly-beta-keto species are synthesized and stabilized, how their chain lengths are determined, and, in particular, how specific cyclization patterns are controlled have been largely inaccessible and functionally unknown until recently. A product template (PT) domain is responsible for controlling specific aldol cyclization and aromatization of these mature polyketide precursors, but the mechanistic basis is unknown. Here we present the 1.8 A crystal structure and mutational studies of a dissected PT monodomain from PksA, the NR-PKS that initiates the biosynthesis of the potent hepatocarcinogen aflatoxin B(1) in Aspergillus parasiticus. Despite having minimal sequence similarity to known enzymes, the structure displays a distinct 'double hot dog' (DHD) fold. Co-crystal structures with palmitate or a bicyclic substrate mimic illustrate that PT can bind both linear and bicyclic polyketides. Docking and mutagenesis studies reveal residues important for substrate binding and catalysis, and identify a phosphopantetheine localization channel and a deep two-part interior binding pocket and reaction chamber. Sequence similarity and extensive conservation of active site residues in PT domains suggest that the mechanistic insights gleaned from these studies will prove general for this class of IPKSs, and lay a foundation for defining the molecular rules controlling NR-PKS cyclization specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872118/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872118/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crawford, Jason M -- Korman, Tyler P -- Labonte, Jason W -- Vagstad, Anna L -- Hill, Eric A -- Kamari-Bidkorpeh, Oliver -- Tsai, Shiou-Chuan -- Townsend, Craig A -- ES001670/ES/NIEHS NIH HHS/ -- R01 GM076330/GM/NIGMS NIH HHS/ -- R01 GM076330-01A2/GM/NIGMS NIH HHS/ -- R01 GM076330-02/GM/NIGMS NIH HHS/ -- R01 GM076330-03/GM/NIGMS NIH HHS/ -- R01 GM100305/GM/NIGMS NIH HHS/ -- R37 AI014937/AI/NIAID NIH HHS/ -- R37 AI014937-31/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Oct 22;461(7267):1139-43. doi: 10.1038/nature08475.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Johns Hopkins University, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847268" target="_blank"〉PubMed〈/a〉
    Keywords: Aflatoxin B1/biosynthesis ; Anthracenes/metabolism ; Anthraquinones/metabolism ; Aspergillus/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Cyclization ; Models, Molecular ; Oxidation-Reduction ; Palmitic Acid/metabolism ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    A secreted complement-control-related protein ensures acetylcholine receptor clustering (2009)
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    Publication Date: 2009-10-02
    Description: Efficient neurotransmission at chemical synapses relies on spatial congruence between the presynaptic active zone, where synaptic vesicles fuse, and the postsynaptic differentiation, where neurotransmitter receptors concentrate. Diverse molecular systems have evolved to localize receptors at synapses, but in most cases, they rely on scaffolding proteins localized below the plasma membrane. A few systems have been suggested to control the synaptic localization of neurotransmitter receptors through extracellular interactions, such as the pentraxins that bind AMPA receptors and trigger their aggregation. However, it is not yet clear whether these systems have a central role in the organization of postsynaptic domains in vivo or rather provide modulatory functions. Here we describe an extracellular scaffold that is necessary to cluster acetylcholine receptors at neuromuscular junctions in the nematode Caenorhabditis elegans. It involves the ectodomain of the previously identified transmembrane protein LEV-10 (ref. 6) and a novel extracellular protein, LEV-9. LEV-9 is secreted by the muscle cells and localizes at cholinergic neuromuscular junctions. Acetylcholine receptors, LEV-9 and LEV-10 are interdependent for proper synaptic localization and physically interact based on biochemical evidence. Notably, the function of LEV-9 relies on eight complement control protein (CCP) domains. These domains, also called 'sushi domains', are usually found in proteins regulating complement activity in the vertebrate immune system. Because the complement system does not exist in protostomes, our results suggest that some of the numerous uncharacterized CCP proteins expressed in the mammalian brain might be directly involved in the organization of the synapse, independently from immune functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gendrel, Marie -- Rapti, Georgia -- Richmond, Janet E -- Bessereau, Jean-Louis -- R01 MH073156/MH/NIMH NIH HHS/ -- England -- Nature. 2009 Oct 15;461(7266):992-6. doi: 10.1038/nature08430. Epub 2009 Sep 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ENS, Biology Department, Paris, F-75005 France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794415" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/cytology/*metabolism ; Caenorhabditis elegans Proteins/*chemistry/genetics/*metabolism/secretion ; Membrane Proteins/genetics/metabolism ; Molecular Sequence Data ; Muscles/metabolism ; Neuromuscular Junction/metabolism ; Organ Specificity ; Protein Binding ; Protein Structure, Tertiary ; Protein Transport ; Receptors, Cholinergic/*metabolism ; Viral Proteins/*chemistry
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    Dynamics of nucleosome remodelling by individual ACF complexes (2009)
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    Publication Date: 2009-12-25
    Description: The ATP-dependent chromatin assembly and remodelling factor (ACF) functions to generate regularly spaced nucleosomes, which are required for heritable gene silencing. The mechanism by which ACF mobilizes nucleosomes remains poorly understood. Here we report a single-molecule FRET study that monitors the remodelling of individual nucleosomes by ACF in real time, revealing previously unknown remodelling intermediates and dynamics. In the presence of ACF and ATP, the nucleosomes exhibit gradual translocation along DNA interrupted by well-defined kinetic pauses that occurred after approximately seven or three to four base pairs of translocation. The binding of ACF, translocation of DNA and exiting of translocation pauses are all ATP-dependent, revealing three distinct functional roles of ATP during remodelling. At equilibrium, a continuously bound ACF complex can move the nucleosome back-and-forth many times before dissociation, indicating that ACF is a highly processive and bidirectional nucleosome translocase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835771/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835771/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blosser, Timothy R -- Yang, Janet G -- Stone, Michael D -- Narlikar, Geeta J -- Zhuang, Xiaowei -- GM073767/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 24;462(7276):1022-7. doi: 10.1038/nature08627.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033040" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; *Chromatin Assembly and Disassembly ; Fluorescence Resonance Energy Transfer ; Humans ; *Models, Molecular ; Nucleosomes/*chemistry ; Protein Structure, Tertiary ; Transcription Factors/*chemistry/*metabolism
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    Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution (2009)
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    Publication Date: 2009-03-28
    Description: Human spliceosomal U1 small nuclear ribonucleoprotein particles (snRNPs), which consist of U1 small nuclear RNA and ten proteins, recognize the 5' splice site within precursor messenger RNAs and initiate the assembly of the spliceosome for intron excision. An electron density map of the functional core of U1 snRNP at 5.5 A resolution has enabled us to build the RNA and, in conjunction with site-specific labelling of individual proteins, to place the seven Sm proteins, U1-C and U1-70K into the map. Here we present the detailed structure of a spliceosomal snRNP, revealing a hierarchical network of intricate interactions between subunits. A striking feature is the amino (N)-terminal polypeptide of U1-70K, which extends over a distance of 180 A from its RNA binding domain, wraps around the core domain consisting of the seven Sm proteins and finally contacts U1-C, which is crucial for 5'-splice-site recognition. The structure of U1 snRNP provides insights into U1 snRNP assembly and suggests a possible mechanism of 5'-splice-site recognition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673513/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673513/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pomeranz Krummel, Daniel A -- Oubridge, Chris -- Leung, Adelaine K W -- Li, Jade -- Nagai, Kiyoshi -- MC_U105184330/Medical Research Council/United Kingdom -- U.1051.04.016(78933)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Mar 26;458(7237):475-80. doi: 10.1038/nature07851.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325628" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Humans ; Models, Biological ; Models, Molecular ; Nucleic Acid Conformation ; Protein Folding ; Protein Structure, Tertiary ; RNA Splice Sites ; RNA Splicing ; RNA, Small Nuclear/chemistry ; Ribonucleoprotein, U1 Small Nuclear/*chemistry/metabolism ; Spliceosomes/*chemistry ; Zinc Fingers
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    Role of the polycomb protein EED in the propagation of repressive histone marks (2009)
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    Publication Date: 2009-09-22
    Description: Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED. Here we show that the carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED that prevent it from recognizing repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772642/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Margueron, Raphael -- Justin, Neil -- Ohno, Katsuhito -- Sharpe, Miriam L -- Son, Jinsook -- Drury, William J 3rd -- Voigt, Philipp -- Martin, Stephen R -- Taylor, William R -- De Marco, Valeria -- Pirrotta, Vincenzo -- Reinberg, Danny -- Gamblin, Steven J -- GM064844/GM/NIGMS NIH HHS/ -- GM37120/GM/NIGMS NIH HHS/ -- MC_U117584222/Medical Research Council/United Kingdom -- R01 GM064844/GM/NIGMS NIH HHS/ -- R01 GM064844-08/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Oct 8;461(7265):762-7. doi: 10.1038/nature08398. Epub 2009 Sep 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, New York University Medical School, 522 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19767730" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Cell Line ; Chromatin/chemistry/*genetics/metabolism ; Crystallography, X-Ray ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/*genetics/growth & development/*metabolism ; Enzyme Activation ; *Gene Silencing ; Histone-Lysine N-Methyltransferase/chemistry/metabolism ; Histones/*chemistry/*metabolism ; Lysine/analogs & derivatives/metabolism ; Methylation ; Models, Biological ; Models, Molecular ; Nuclear Proteins/metabolism ; Nucleosomes/chemistry/genetics/metabolism ; Polycomb Repressive Complex 2 ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/chemistry/genetics/*metabolism ; Substrate Specificity
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    Structural biology: Spliceosome subunit revealed (2009)
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    Publication Date: 2009-03-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Query, Charles C -- R01 GM057829/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):418-9. doi: 10.1038/458418a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325619" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Humans ; Introns/genetics ; Protein Structure, Tertiary ; RNA Splicing ; RNA, Small Nuclear/chemistry ; Ribonucleoprotein, U1 Small Nuclear/*chemistry/genetics/metabolism ; Spliceosomes/*chemistry/genetics/metabolism
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    A phylogeny-driven genomic encyclopaedia of Bacteria and Archaea (2009)
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    Publication Date: 2009-12-25
    Description: Sequencing of bacterial and archaeal genomes has revolutionized our understanding of the many roles played by microorganisms. There are now nearly 1,000 completed bacterial and archaeal genomes available, most of which were chosen for sequencing on the basis of their physiology. As a result, the perspective provided by the currently available genomes is limited by a highly biased phylogenetic distribution. To explore the value added by choosing microbial genomes for sequencing on the basis of their evolutionary relationships, we have sequenced and analysed the genomes of 56 culturable species of Bacteria and Archaea selected to maximize phylogenetic coverage. Analysis of these genomes demonstrated pronounced benefits (compared to an equivalent set of genomes randomly selected from the existing database) in diverse areas including the reconstruction of phylogenetic history, the discovery of new protein families and biological properties, and the prediction of functions for known genes from other organisms. Our results strongly support the need for systematic 'phylogenomic' efforts to compile a phylogeny-driven 'Genomic Encyclopedia of Bacteria and Archaea' in order to derive maximum knowledge from existing microbial genome data as well as from genome sequences to come.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073058/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073058/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Dongying -- Hugenholtz, Philip -- Mavromatis, Konstantinos -- Pukall, Rudiger -- Dalin, Eileen -- Ivanova, Natalia N -- Kunin, Victor -- Goodwin, Lynne -- Wu, Martin -- Tindall, Brian J -- Hooper, Sean D -- Pati, Amrita -- Lykidis, Athanasios -- Spring, Stefan -- Anderson, Iain J -- D'haeseleer, Patrik -- Zemla, Adam -- Singer, Mitchell -- Lapidus, Alla -- Nolan, Matt -- Copeland, Alex -- Han, Cliff -- Chen, Feng -- Cheng, Jan-Fang -- Lucas, Susan -- Kerfeld, Cheryl -- Lang, Elke -- Gronow, Sabine -- Chain, Patrick -- Bruce, David -- Rubin, Edward M -- Kyrpides, Nikos C -- Klenk, Hans-Peter -- Eisen, Jonathan A -- R01 GM054592-09/GM/NIGMS NIH HHS/ -- R01 GM067012-04/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1056-60. doi: 10.1038/nature08656.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DOE Joint Genome Institute, Walnut Creek, California 94598, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033048" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/chemistry ; Amino Acid Sequence ; Archaea/*classification/*genetics ; Bacteria/*classification/*genetics ; Bacterial Proteins/chemistry ; Biodiversity ; Databases, Genetic ; Genes, rRNA/genetics ; Genome, Archaeal/*genetics ; Genome, Bacterial/*genetics ; Models, Molecular ; Molecular Sequence Data ; *Phylogeny ; Protein Structure, Tertiary ; Sequence Alignment
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    The chromatin remodeller ACF acts as a dimeric motor to space nucleosomes (2009)
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    Details
    Publication Date: 2009-12-25
    Description: Evenly spaced nucleosomes directly correlate with condensed chromatin and gene silencing. The ATP-dependent chromatin assembly factor (ACF) forms such structures in vitro and is required for silencing in vivo. ACF generates and maintains nucleosome spacing by constantly moving a nucleosome towards the longer flanking DNA faster than the shorter flanking DNA. How the enzyme rapidly moves back and forth between both sides of a nucleosome to accomplish bidirectional movement is unknown. Here we show that nucleosome movement depends cooperatively on two ACF molecules, indicating that ACF functions as a dimer of ATPases. Further, the nucleotide state determines whether the dimer closely engages one or both sides of the nucleosome. Three-dimensional reconstruction by single-particle electron microscopy of the ATPase-nucleosome complex in an activated ATP state reveals a dimer architecture in which the two ATPases face each other. Our results indicate a model in which the two ATPases work in a coordinated manner, taking turns to engage either side of a nucleosome, thereby allowing processive bidirectional movement. This novel dimeric motor mechanism differs from that of dimeric motors such as kinesin and dimeric helicases that processively translocate unidirectionally and reflects the unique challenges faced by motors that move nucleosomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869534/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869534/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Racki, Lisa R -- Yang, Janet G -- Naber, Nariman -- Partensky, Peretz D -- Acevedo, Ashley -- Purcell, Thomas J -- Cooke, Roger -- Cheng, Yifan -- Narlikar, Geeta J -- R01 GM073767/GM/NIGMS NIH HHS/ -- R01 GM073767-01/GM/NIGMS NIH HHS/ -- R01 GM073767-02/GM/NIGMS NIH HHS/ -- R01 GM073767-03/GM/NIGMS NIH HHS/ -- R01 GM073767-03S1/GM/NIGMS NIH HHS/ -- R01 GM073767-04/GM/NIGMS NIH HHS/ -- R01 GM073767-05/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1016-21. doi: 10.1038/nature08621.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033039" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Cell Line ; Chromatin Assembly and Disassembly/*physiology ; Dimerization ; Gene Silencing/physiology ; Histones/metabolism ; Humans ; Microscopy, Electron, Transmission ; *Models, Molecular ; Multiprotein Complexes/*metabolism ; Nucleosomes/chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Transcription Factors/chemistry/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 40
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    A dimerization-dependent mechanism drives RAF catalytic activation (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-09-04
    Description: The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival. Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phosphorylation events that activate MEK, and in turn ERK. Unbridled signalling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF has been linked to several human cancers. Of note, one member of the RAF family, BRAF, is the most frequently mutated oncogene in the kinase superfamily. Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. In particular, the process by which the RAF kinase domain becomes activated towards its substrate MEK remains of topical interest. Here, using Drosophila Schneider S2 cells, we demonstrate that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which we term the side-to-side dimer. Moreover, we find that the RAF-related pseudo-kinase KSR (kinase suppressor of Ras) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rajakulendran, Thanashan -- Sahmi, Malha -- Lefrancois, Martin -- Sicheri, Frank -- Therrien, Marc -- England -- Nature. 2009 Sep 24;461(7263):542-5. doi: 10.1038/nature08314. Epub 2009 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727074" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Biocatalysis ; Cell Line ; Drosophila Proteins/*chemistry/genetics/*metabolism ; Drosophila melanogaster/*enzymology ; Enzyme Activation ; Humans ; Models, Molecular ; Protein Kinases/chemistry/metabolism ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism ; Proto-Oncogene Proteins c-raf/*chemistry/genetics/*metabolism ; Structure-Activity Relationship
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 41
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    Structure and function of the 5'--〉3' exoribonuclease Rat1 and its activating partner Rai1 (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: The 5'--〉3' exoribonucleases (XRNs) comprise a large family of conserved enzymes in eukaryotes with crucial functions in RNA metabolism and RNA interference. XRN2, or Rat1 in yeast, functions primarily in the nucleus and also has an important role in transcription termination by RNA polymerase II (refs 7-14). Rat1 exoribonuclease activity is stimulated by the protein Rai1 (refs 15, 16). Here we report the crystal structure at 2.2 A resolution of Schizosaccharomyces pombe Rat1 in complex with Rai1, as well as the structures of Rai1 and its murine homologue Dom3Z alone at 2.0 A resolution. The structures reveal the molecular mechanism for the activation of Rat1 by Rai1 and for the exclusive exoribonuclease activity of Rat1. Biochemical studies confirm these observations, and show that Rai1 allows Rat1 to degrade RNAs with stable secondary structure more effectively. There are large differences in the active site landscape of Rat1 compared to related and PIN (PilT N terminus) domain-containing nucleases. Unexpectedly, we identified a large pocket in Rai1 and Dom3Z that contains highly conserved residues, including three acidic side chains that coordinate a divalent cation. Mutagenesis and biochemical studies demonstrate that Rai1 possesses pyrophosphohydrolase activity towards 5' triphosphorylated RNA. Such an activity is important for messenger RNA degradation in bacteria, but this is, to our knowledge, the first demonstration of this activity in eukaryotes and suggests that Rai1/Dom3Z may have additional important functions in RNA metabolism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739979/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiang, Song -- Cooper-Morgan, Amalene -- Jiao, Xinfu -- Kiledjian, Megerditch -- Manley, James L -- Tong, Liang -- GM077175/GM/NIGMS NIH HHS/ -- GM28983/GM/NIGMS NIH HHS/ -- GM67005/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM067005/GM/NIGMS NIH HHS/ -- R01 GM067005-01A2/GM/NIGMS NIH HHS/ -- R01 GM077175/GM/NIGMS NIH HHS/ -- R01 GM077175-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 9;458(7239):784-8. doi: 10.1038/nature07731. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Columbia University, New York, New York 10027, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194460" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Exoribonucleases/*chemistry/genetics/*metabolism ; Mice ; *Models, Molecular ; Mutation ; *Nuclear Proteins/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/metabolism ; *Schizosaccharomyces/chemistry/enzymology/genetics ; Schizosaccharomyces pombe Proteins/*chemistry/genetics/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 42
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    A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-12-08
    Description: Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Edwards, Marcus J -- Flatman, Ruth H -- Mitchenall, Lesley A -- Stevenson, Clare E M -- Le, Tung B K -- Clarke, Thomas A -- McKay, Adam R -- Fiedler, Hans-Peter -- Buttner, Mark J -- Lawson, David M -- Maxwell, Anthony -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2009 Dec 4;326(5958):1415-8. doi: 10.1126/science.1179123.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, John Innes Centre, Colney, Norwich NR4 7UH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19965760" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Anti-Bacterial Agents/chemistry/metabolism/pharmacology ; Binding Sites ; Coumarins/chemistry/metabolism/pharmacology ; Crystallography, X-Ray ; DNA Gyrase/*chemistry/genetics/*metabolism ; DNA, Bacterial/metabolism ; Drug Resistance, Bacterial ; Escherichia coli/drug effects/*enzymology/genetics ; Glycosides/chemistry/metabolism/pharmacology ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Molecular Weight ; Mutagenesis, Site-Directed ; Mutation ; Protein Multimerization ; Protein Structure, Tertiary ; Topoisomerase II Inhibitors
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 43
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    Structural basis of transcription: backtracked RNA polymerase II at 3.4 angstrom resolution (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-05-30
    Description: Transcribing RNA polymerases oscillate between three stable states, two of which, pre- and posttranslocated, were previously subjected to x-ray crystal structure determination. We report here the crystal structure of RNA polymerase II in the third state, the reverse translocated, or "backtracked" state. The defining feature of the backtracked structure is a binding site for the first backtracked nucleotide. This binding site is occupied in case of nucleotide misincorporation in the RNA or damage to the DNA, and is termed the "P" site because it supports proofreading. The predominant mechanism of proofreading is the excision of a dinucleotide in the presence of the elongation factor SII (TFIIS). Structure determination of a cocrystal with TFIIS reveals a rearrangement whereby cleavage of the RNA may take place.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718261/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718261/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Dong -- Bushnell, David A -- Huang, Xuhui -- Westover, Kenneth D -- Levitt, Michael -- Kornberg, Roger D -- GM036559/GM/NIGMS NIH HHS/ -- GM041455/GM/NIGMS NIH HHS/ -- GM049985/GM/NIGMS NIH HHS/ -- K99 GM085136/GM/NIGMS NIH HHS/ -- K99 GM085136-01/GM/NIGMS NIH HHS/ -- R00 GM085136/GM/NIGMS NIH HHS/ -- R01 GM036659/GM/NIGMS NIH HHS/ -- R01 GM041455/GM/NIGMS NIH HHS/ -- R01 GM049985/GM/NIGMS NIH HHS/ -- R01 GM049985-16/GM/NIGMS NIH HHS/ -- R37 GM036659/GM/NIGMS NIH HHS/ -- R37 GM036659-22/GM/NIGMS NIH HHS/ -- R37 GM041455/GM/NIGMS NIH HHS/ -- R37 GM041455-20/GM/NIGMS NIH HHS/ -- U54 GM072970/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 May 29;324(5931):1203-6. doi: 10.1126/science.1168729.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19478184" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pair Mismatch ; Crystallography, X-Ray ; Guanosine Monophosphate/chemistry/metabolism ; Models, Molecular ; Nucleic Acid Conformation ; Oligoribonucleotides/chemistry/*metabolism ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; RNA/chemistry/*metabolism ; RNA Polymerase II/*chemistry/*metabolism ; Saccharomyces cerevisiae/*enzymology ; *Transcription, Genetic ; Transcriptional Elongation Factors/chemistry/*metabolism
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    Structure of the anaphase-promoting complex/cyclosome interacting with a mitotic checkpoint complex (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-17
    Description: Once all chromosomes are connected to the mitotic spindle (bioriented), anaphase is initiated by the protein ubiquitylation activity of the anaphase-promoting complex/cyclosome (APC/C) and its coactivator Cdc20 (APC/C(Cdc20)). Before chromosome biorientation, anaphase is delayed by a mitotic checkpoint complex (MCC) that inhibits APC/C(Cdc20). We used single-particle electron microscopy to obtain three-dimensional models of human APC/C in various functional states: bound to MCC, to Cdc20, or to neither (apo-APC/C). These experiments revealed that MCC associates with the Cdc20 binding site on APC/C, locks the otherwise flexible APC/C in a "closed" state, and prevents binding and ubiquitylation of a wide range of different APC/C substrates. These observations clarify the structural basis for the inhibition of APC/C by spindle checkpoint proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989460/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989460/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herzog, Franz -- Primorac, Ivana -- Dube, Prakash -- Lenart, Peter -- Sander, Bjorn -- Mechtler, Karl -- Stark, Holger -- Peters, Jan-Michael -- F 3407/Austrian Science Fund FWF/Austria -- New York, N.Y. -- Science. 2009 Mar 13;323(5920):1477-81. doi: 10.1126/science.1163300.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19286556" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Anaphase-Promoting Complex-Cyclosome ; Cdc20 Proteins ; Cell Cycle Proteins/chemistry/metabolism ; HeLa Cells ; Humans ; Image Processing, Computer-Assisted ; Imaging, Three-Dimensional ; Microscopy, Electron ; *Mitosis ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Spindle Apparatus/*metabolism ; Ubiquitin-Conjugating Enzymes/chemistry/metabolism ; Ubiquitin-Protein Ligase Complexes/*chemistry/*metabolism ; Ubiquitination
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    Structure of rotavirus outer-layer protein VP7 bound with a neutralizing Fab (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-06-13
    Description: Rotavirus outer-layer protein VP7 is a principal target of protective antibodies. Removal of free calcium ions (Ca2+) dissociates VP7 trimers into monomers, releasing VP7 from the virion, and initiates penetration-inducing conformational changes in the other outer-layer protein, VP4. We report the crystal structure at 3.4 angstrom resolution of VP7 bound with the Fab fragment of a neutralizing monoclonal antibody. The Fab binds across the outer surface of the intersubunit contact, which contains two Ca2+ sites. Mutations that escape neutralization by other antibodies suggest that the same region bears the epitopes of most neutralizing antibodies. The monovalent Fab is sufficient to neutralize infectivity. We propose that neutralizing antibodies against VP7 act by stabilizing the trimer, thereby inhibiting the uncoating trigger for VP4 rearrangement. A disulfide-linked trimer is a potential subunit immunogen.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995306/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aoki, Scott T -- Settembre, Ethan C -- Trask, Shane D -- Greenberg, Harry B -- Harrison, Stephen C -- Dormitzer, Philip R -- AI-21362/AI/NIAID NIH HHS/ -- CA-13202/CA/NCI NIH HHS/ -- DK-56339/DK/NIDDK NIH HHS/ -- R37 CA013202/CA/NCI NIH HHS/ -- R37 CA013202-38/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Jun 12;324(5933):1444-7. doi: 10.1126/science.1170481.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19520960" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/immunology/metabolism ; Antibodies, Viral/chemistry/*immunology/metabolism ; Antigens, Viral/*chemistry/genetics/*immunology/metabolism ; Binding Sites ; Binding Sites, Antibody ; Calcium/metabolism ; Capsid Proteins/*chemistry/genetics/*immunology/metabolism ; Crystallography, X-Ray ; Epitopes/immunology ; Immunoglobulin Fab Fragments/chemistry/*immunology/metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neutralization Tests ; Protein Folding ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Subunits ; Recombinant Proteins/chemistry ; Rotavirus/*chemistry/immunology ; Serotyping
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    Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-28
    Description: P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of approximately 6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720052/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720052/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aller, Stephen G -- Yu, Jodie -- Ward, Andrew -- Weng, Yue -- Chittaboina, Srinivas -- Zhuo, Rupeng -- Harrell, Patina M -- Trinh, Yenphuong T -- Zhang, Qinghai -- Urbatsch, Ina L -- Chang, Geoffrey -- F32 GM078914/GM/NIGMS NIH HHS/ -- F32 GM078914-03/GM/NIGMS NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM078914/GM/NIGMS NIH HHS/ -- GM61905/GM/NIGMS NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-050002/GM/NIGMS NIH HHS/ -- R01 GM061905/GM/NIGMS NIH HHS/ -- R01 GM061905-09/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Mar 27;323(5922):1718-22. doi: 10.1126/science.1168750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325113" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Animals ; Apoproteins/chemistry/metabolism ; Binding Sites ; Cell Membrane/chemistry ; Crystallography, X-Ray ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/chemistry ; Mice ; Models, Molecular ; Molecular Sequence Data ; P-Glycoprotein/antagonists & inhibitors/*chemistry/*metabolism ; Peptides, Cyclic/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Stereoisomerism ; Verapamil/metabolism/pharmacology
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  • 47
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    DNA binding site sequence directs glucocorticoid receptor structure and activity (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-04-18
    Description: Genes are not simply turned on or off, but instead their expression is fine-tuned to meet the needs of a cell. How genes are modulated so precisely is not well understood. The glucocorticoid receptor (GR) regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes. Traditionally, these binding sites have been viewed only as docking sites. Using structural, biochemical, and cell-based assays, we show that GR binding sequences, differing by as little as a single base pair, differentially affect GR conformation and regulatory activity. We therefore propose that DNA is a sequence-specific allosteric ligand of GR that tailors the activity of the receptor toward specific target genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777810/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777810/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meijsing, Sebastiaan H -- Pufall, Miles A -- So, Alex Y -- Bates, Darren L -- Chen, Lin -- Yamamoto, Keith R -- GM08537/GM/NIGMS NIH HHS/ -- R01 CA020535/CA/NCI NIH HHS/ -- R01 CA020535-31/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Apr 17;324(5925):407-10. doi: 10.1126/science.1164265.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19372434" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Cell Line, Tumor ; Crystallography, X-Ray ; DNA/*chemistry/*metabolism ; Humans ; Ligands ; Models, Molecular ; Mutation ; Protein Conformation ; Protein Isoforms/chemistry/metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Rats ; Receptors, Glucocorticoid/chemistry/genetics/*metabolism ; Transcriptional Activation
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    Diversity and complexity in DNA recognition by transcription factors (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-05-16
    Description: Sequence preferences of DNA binding proteins are a primary mechanism by which cells interpret the genome. Despite the central importance of these proteins in physiology, development, and evolution, comprehensive DNA binding specificities have been determined experimentally for only a few proteins. Here, we used microarrays containing all 10-base pair sequences to examine the binding specificities of 104 distinct mouse DNA binding proteins representing 22 structural classes. Our results reveal a complex landscape of binding, with virtually every protein analyzed possessing unique preferences. Roughly half of the proteins each recognized multiple distinctly different sequence motifs, challenging our molecular understanding of how proteins interact with their DNA binding sites. This complexity in DNA recognition may be important in gene regulation and in the evolution of transcriptional regulatory networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905877/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905877/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Badis, Gwenael -- Berger, Michael F -- Philippakis, Anthony A -- Talukder, Shaheynoor -- Gehrke, Andrew R -- Jaeger, Savina A -- Chan, Esther T -- Metzler, Genita -- Vedenko, Anastasia -- Chen, Xiaoyu -- Kuznetsov, Hanna -- Wang, Chi-Fong -- Coburn, David -- Newburger, Daniel E -- Morris, Quaid -- Hughes, Timothy R -- Bulyk, Martha L -- R01 HG003985/HG/NHGRI NIH HHS/ -- R01 HG003985-01/HG/NHGRI NIH HHS/ -- R01 HG003985-02/HG/NHGRI NIH HHS/ -- R01 HG003985-03/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2009 Jun 26;324(5935):1720-3. doi: 10.1126/science.1162327. Epub 2009 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19443739" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; DNA/chemistry/*metabolism ; Electrophoretic Mobility Shift Assay ; Gene Expression Regulation ; Gene Regulatory Networks ; Humans ; Mice ; Protein Array Analysis ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/chemistry/metabolism ; Transcription Factors/*chemistry/*metabolism
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    Paternal control of embryonic patterning in Arabidopsis thaliana (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-17
    Description: The YODA (YDA) mitogen-activated protein kinase pathway promotes elongation of the Arabidopsis zygote and development of its basal daughter cell into the extra-embryonic suspensor. Here, we show that the interleukin-1 receptor-associated kinase (IRAK)/Pelle-like kinase gene SHORT SUSPENSOR (SSP) regulates this pathway through a previously unknown parent-of-origin effect. SSP transcripts are produced in mature pollen but do not appear to be translated. Instead, they are delivered via the sperm cells to the zygote and the endosperm, where SSP protein transiently accumulates. Ectopic expression of SSP protein in the leaf epidermis is sufficient to activate YDA-dependent signaling. We propose that SSP protein produced from paternal transcripts upon fertilization triggers zygotic YDA activity, providing an essential temporal cue for the regulation of the asymmetric first division.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bayer, Martin -- Nawy, Tal -- Giglione, Carmela -- Galli, Mary -- Meinnel, Thierry -- Lukowitz, Wolfgang -- New York, N.Y. -- Science. 2009 Mar 13;323(5920):1485-8. doi: 10.1126/science.1167784.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19286558" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Arabidopsis/*embryology/*genetics/metabolism ; Arabidopsis Proteins/*metabolism ; Biocatalysis ; Catalytic Domain ; Cell Division ; Crosses, Genetic ; *Gene Expression Regulation, Plant ; Genomic Imprinting ; Interleukin-1 Receptor-Associated Kinases/chemistry/*genetics/*metabolism ; MAP Kinase Kinase Kinases/*metabolism ; MAP Kinase Signaling System ; Mutation ; Plants, Genetically Modified ; Pollen/metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA, Messenger/genetics/metabolism ; Recombinant Fusion Proteins ; Seeds/growth & development/metabolism ; Transcription, Genetic
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    S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-04-04
    Description: Mitochondria continuously undergo two opposing processes, fission and fusion. The disruption of this dynamic equilibrium may herald cell injury or death and may contribute to developmental and neurodegenerative disorders. Nitric oxide functions as a signaling molecule, but in excess it mediates neuronal injury, in part via mitochondrial fission or fragmentation. However, the underlying mechanism for nitric oxide-induced pathological fission remains unclear. We found that nitric oxide produced in response to beta-amyloid protein, thought to be a key mediator of Alzheimer's disease, triggered mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of dynamin-related protein 1 (forming SNO-Drp1). Preventing nitrosylation of Drp1 by cysteine mutation abrogated these neurotoxic events. SNO-Drp1 is increased in brains of human Alzheimer's disease patients and may thus contribute to the pathogenesis of neurodegeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823371/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823371/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Dong-Hyung -- Nakamura, Tomohiro -- Fang, Jianguo -- Cieplak, Piotr -- Godzik, Adam -- Gu, Zezong -- Lipton, Stuart A -- P01 ES016738/ES/NIEHS NIH HHS/ -- P01 ES016738-01/ES/NIEHS NIH HHS/ -- P01 ES016738-010003/ES/NIEHS NIH HHS/ -- P01 ES016738-02/ES/NIEHS NIH HHS/ -- P01 ES016738-020003/ES/NIEHS NIH HHS/ -- P01 HD029587/HD/NICHD NIH HHS/ -- P01 HD029587-16/HD/NICHD NIH HHS/ -- P01 HD29587/HD/NICHD NIH HHS/ -- P30 NS057096/NS/NINDS NIH HHS/ -- P30 NS057096-04/NS/NINDS NIH HHS/ -- R01 EY005477/EY/NEI NIH HHS/ -- R01 EY005477-25/EY/NEI NIH HHS/ -- R01 EY05477/EY/NEI NIH HHS/ -- New York, N.Y. -- Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19342591" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism/pathology ; Amino Acid Motifs ; Amyloid beta-Peptides/*metabolism/pharmacology ; Animals ; Cell Line ; Cell Line, Tumor ; Cerebral Cortex/cytology ; Cysteine/analogs & derivatives/genetics/metabolism/pharmacology ; Female ; GTP Phosphohydrolases/chemistry/*metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; Microtubule-Associated Proteins/chemistry/*metabolism ; Mitochondria/drug effects/physiology/*ultrastructure ; Mitochondrial Proteins/chemistry/*metabolism ; Models, Molecular ; Mutation ; Neurons/drug effects/*ultrastructure ; Nitric Oxide/*metabolism ; Peptide Fragments/metabolism/pharmacology ; Protein Multimerization ; Protein Structure, Tertiary ; S-Nitrosothiols/pharmacology
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    Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-09-26
    Description: To explore the mechanisms and evolution of cell-cycle control, we analyzed the position and conservation of large numbers of phosphorylation sites for the cyclin-dependent kinase Cdk1 in the budding yeast Saccharomyces cerevisiae. We combined specific chemical inhibition of Cdk1 with quantitative mass spectrometry to identify the positions of 547 phosphorylation sites on 308 Cdk1 substrates in vivo. Comparisons of these substrates with orthologs throughout the ascomycete lineage revealed that the position of most phosphorylation sites is not conserved in evolution; instead, clusters of sites shift position in rapidly evolving disordered regions. We propose that the regulation of protein function by phosphorylation often depends on simple nonspecific mechanisms that disrupt or enhance protein-protein interactions. The gain or loss of phosphorylation sites in rapidly evolving regions could facilitate the evolution of kinase-signaling circuits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813701/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813701/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Holt, Liam J -- Tuch, Brian B -- Villen, Judit -- Johnson, Alexander D -- Gygi, Steven P -- Morgan, David O -- GM037049/GM/NIGMS NIH HHS/ -- GM50684/GM/NIGMS NIH HHS/ -- HG3456/HG/NHGRI NIH HHS/ -- R01 GM069901/GM/NIGMS NIH HHS/ -- R01 GM069901-06/GM/NIGMS NIH HHS/ -- R01 HG003456/HG/NHGRI NIH HHS/ -- R01 HG003456-06/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2009 Sep 25;325(5948):1682-6. doi: 10.1126/science.1172867.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Physiology and Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779198" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Ascomycota/chemistry/genetics/metabolism ; *Biological Evolution ; CDC2 Protein Kinase/antagonists & inhibitors/*metabolism ; *Cell Cycle ; Cell Physiological Processes ; Computational Biology ; *Evolution, Molecular ; Molecular Sequence Data ; Phosphopeptides/chemistry/*metabolism ; Phosphorylation ; Phylogeny ; Protein Conformation ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; *Signal Transduction ; Substrate Specificity
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    CD24 and Siglec-10 selectively repress tissue damage-induced immune responses (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-07
    Description: Patten recognition receptors, which recognize pathogens or components of injured cells (danger), trigger activation of the innate immune system. Whether and how the host distinguishes between danger- versus pathogen-associated molecular patterns remains unresolved. We report that CD24-deficient mice exhibit increased susceptibility to danger- but not pathogen-associated molecular patterns. CD24 associates with high mobility group box 1, heat shock protein 70, and heat shock protein 90; negatively regulates their stimulatory activity; and inhibits nuclear factor kappaB (NF-kappaB) activation. This occurs at least in part through CD24 association with Siglec-10 in humans or Siglec-G in mice. Our results reveal that the CD24-Siglec G pathway protects the host against a lethal response to pathological cell death and discriminates danger- versus pathogen-associated molecular patterns.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Guo-Yun -- Tang, Jie -- Zheng, Pan -- Liu, Yang -- AI064350/AI/NIAID NIH HHS/ -- CA112001/CA/NCI NIH HHS/ -- CA58033/CA/NCI NIH HHS/ -- R01 AI064350/AI/NIAID NIH HHS/ -- R01 AI064350-04/AI/NIAID NIH HHS/ -- R01 CA058033/CA/NCI NIH HHS/ -- R01 CA058033-16A2/CA/NCI NIH HHS/ -- R01 CA112001/CA/NCI NIH HHS/ -- R01 CA112001-02/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Mar 27;323(5922):1722-5. doi: 10.1126/science.1168988. Epub 2009 Mar 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19264983" target="_blank"〉PubMed〈/a〉
    Keywords: Acetaminophen/toxicity ; Animals ; Antigens, CD24/genetics/*metabolism ; Cytokines/metabolism ; Dendritic Cells/immunology ; HMGB1 Protein/chemistry/immunology/*metabolism ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; *Immunity, Innate ; Immunoprecipitation ; Inflammation/*immunology ; Lectins/*metabolism ; Lipopolysaccharides/toxicity ; Liver/immunology/pathology ; Mice ; Mutant Proteins/chemistry/metabolism ; Necrosis/chemically induced/immunology ; Protein Structure, Tertiary ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Receptors, Antigen, B-Cell/*metabolism ; Receptors, Cell Surface/metabolism ; Receptors, Pattern Recognition/immunology/metabolism ; Signal Transduction ; Transcription Factor RelA/metabolism
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    A cytidine deaminase edits C to U in transfer RNAs in Archaea (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-05-02
    Description: All canonical transfer RNAs (tRNAs) have a uridine at position 8, involved in maintaining tRNA tertiary structure. However, the hyperthermophilic archaeon Methanopyrus kandleri harbors 30 (out of 34) tRNA genes with cytidine at position 8. Here, we demonstrate C-to-U editing at this location in the tRNA's tertiary core, and present the crystal structure of a tRNA-specific cytidine deaminase, CDAT8, which has the cytidine deaminase domain linked to a tRNA-binding THUMP domain. CDAT8 is specific for C deamination at position 8, requires only the acceptor stem hairpin for activity, and belongs to a unique family within the "cytidine deaminase-like" superfamily. The presence of this C-to-U editing enzyme guarantees the proper folding and functionality of all M. kandleri tRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857566/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857566/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Randau, Lennart -- Stanley, Bradford J -- Kohlway, Andrew -- Mechta, Sarah -- Xiong, Yong -- Soll, Dieter -- AI078831/AI/NIAID NIH HHS/ -- GM22854/GM/NIGMS NIH HHS/ -- R01 GM022854/GM/NIGMS NIH HHS/ -- R01 GM022854-33/GM/NIGMS NIH HHS/ -- R33 AI078831/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2009 May 1;324(5927):657-9. doi: 10.1126/science.1170123.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. lennart.randau@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19407206" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Catalytic Domain ; Crystallography, X-Ray ; Cytidine Deaminase/*chemistry/*metabolism ; Deamination ; Euryarchaeota/enzymology/genetics/*metabolism ; Genes, Archaeal ; Models, Chemical ; Models, Molecular ; Nucleic Acid Conformation ; Protein Multimerization ; Protein Structure, Tertiary ; *RNA Editing ; RNA, Archaeal/chemistry/genetics/*metabolism ; RNA, Transfer/chemistry/genetics/*metabolism
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    The structure of the ribosome with elongation factor G trapped in the posttranslocational state (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-10-17
    Description: Elongation factor G (EF-G) is a guanosine triphosphatase (GTPase) that plays a crucial role in the translocation of transfer RNAs (tRNAs) and messenger RNA (mRNA) during translation by the ribosome. We report a crystal structure refined to 3.6 angstrom resolution of the ribosome trapped with EF-G in the posttranslocational state using the antibiotic fusidic acid. Fusidic acid traps EF-G in a conformation intermediate between the guanosine triphosphate and guanosine diphosphate forms. The interaction of EF-G with ribosomal elements implicated in stimulating catalysis, such as the L10-L12 stalk and the L11 region, and of domain IV of EF-G with the tRNA at the peptidyl-tRNA binding site (P site) and with mRNA shed light on the role of these elements in EF-G function. The stabilization of the mobile stalks of the ribosome also results in a more complete description of its structure.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763468/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763468/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Yong-Gui -- Selmer, Maria -- Dunham, Christine M -- Weixlbaumer, Albert -- Kelley, Ann C -- Ramakrishnan, V -- 082086/Wellcome Trust/United Kingdom -- MC_U105184332/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2009 Oct 30;326(5953):694-9. doi: 10.1126/science.1179709.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19833919" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry ; Catalysis ; Crystallography, X-Ray ; Fusidic Acid/chemistry/pharmacology ; Models, Molecular ; Peptide Elongation Factor G/*chemistry ; Protein Biosynthesis ; Protein Conformation ; Protein Structure, Tertiary ; Protein Synthesis Inhibitors/chemistry/pharmacology ; RNA, Bacterial/chemistry ; RNA, Messenger/chemistry ; RNA, Transfer/chemistry ; Ribosomes/*chemistry ; Thermus thermophilus
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    Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-11-07
    Description: The LKB1 tumor suppressor is a protein kinase that controls the activity of adenosine monophosphate-activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRADalpha and the scaffolding protein MO25alpha through an unknown, phosphorylation-independent, mechanism. We describe the structure of the core heterotrimeric LKB1-STRADalpha-MO25alpha complex, revealing an unusual allosteric mechanism of LKB1 activation. STRADalpha adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRADalpha and MO25alpha promote the active conformation of LKB1, which is stabilized by MO25alpha interacting with the LKB1 activation loop. This previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases. The structure also reveals how mutations found in Peutz-Jeghers syndrome and in various sporadic cancers impair LKB1 function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518268/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518268/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zeqiraj, Elton -- Filippi, Beatrice Maria -- Deak, Maria -- Alessi, Dario R -- van Aalten, Daan M F -- 087590/Wellcome Trust/United Kingdom -- C33794/A10969/Cancer Research UK/United Kingdom -- G0900138/Medical Research Council/United Kingdom -- MC_U127070193/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2009 Dec 18;326(5960):1707-11. doi: 10.1126/science.1178377. Epub 2009 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19892943" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/metabolism ; Adaptor Proteins, Vesicular Transport/*chemistry/metabolism ; Allosteric Regulation ; Amino Acid Sequence ; Binding Sites ; Calcium-Binding Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/metabolism ; Mutant Proteins/chemistry/metabolism ; Mutation ; Phosphorylation ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry/metabolism
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    The aryl hydrocarbon nuclear translocator alters CD30-mediated NF-kappaB-dependent transcription (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-01-10
    Description: Expression and signaling of CD30, a tumor necrosis factor receptor family member, is up-regulated in numerous lymphoid-derived neoplasias, most notably anaplastic large-cell lymphoma (ALCL) and Hodgkin's lymphoma. To gain insight into the mechanism of CD30 signaling, we used an affinity purification strategy that led to the identification of the aryl hydrocarbon receptor nuclear translocator (ARNT) as a CD30-interacting protein that modulated the activity of the RelB subunit of the transcription factor nuclear factor kappaB (NF-kappaB). ALCL cells that were deficient in ARNT exhibited defects in RelB recruitment to NF-kappaB-responsive promoters, whereas RelA recruitment to the same sites was potentiated, resulting in the augmented expression of these NF-kappaB-responsive genes. These findings indicate that ARNT functions in concert with RelB in a CD30-induced negative feedback mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682336/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682336/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wright, Casey W -- Duckett, Colin S -- R01 GM067827/GM/NIGMS NIH HHS/ -- R01 GM067827-04/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Jan 9;323(5911):251-5. doi: 10.1126/science.1162818.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19131627" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antigens, CD30/*metabolism ; Aryl Hydrocarbon Receptor Nuclear Translocator/chemistry/genetics/*metabolism ; Cell Line ; Cell Line, Tumor ; DNA/metabolism ; Feedback, Physiological ; Gene Expression Regulation ; Humans ; Lymphoma, Large-Cell, Anaplastic/genetics/metabolism ; Molecular Sequence Data ; NF-kappa B/genetics/metabolism ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Receptors, Tumor Necrosis Factor, Type II/metabolism ; Recombinant Fusion Proteins/metabolism ; Signal Transduction ; Transcription Factor RelB/genetics/*metabolism ; *Transcription, Genetic ; Transcriptional Activation
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    Biochemistry. Force signaling in biology (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-06-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gebhardt, J Christof M -- Rief, Matthias -- New York, N.Y. -- Science. 2009 Jun 5;324(5932):1278-80. doi: 10.1126/science.1175874.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Physik Department E22, Technische Universitat Munchen, James-Franck-Strasse, 85748 Munchen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19498156" target="_blank"〉PubMed〈/a〉
    Keywords: ADAM Proteins/*metabolism ; Binding Sites ; Blood Coagulation/physiology ; Hemostasis/*physiology ; Humans ; *Mechanical Phenomena ; Optical Tweezers ; Protein Conformation ; Protein Folding ; Protein Multimerization ; Protein Structure, Tertiary ; Stress, Mechanical ; von Willebrand Factor/*chemistry/*metabolism
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    The extracellular matrix: not just pretty fibrils (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-12-08
    Description: The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing structural support. ECM proteins typically include multiple, independently folded domains whose sequences and arrangement are highly conserved. Some of these domains bind adhesion receptors such as integrins that mediate cell-matrix adhesion and also transduce signals into cells. However, ECM proteins also bind soluble growth factors and regulate their distribution, activation, and presentation to cells. As organized, solid-phase ligands, ECM proteins can integrate complex, multivalent signals to cells in a spatially patterned and regulated fashion. These properties need to be incorporated into considerations of the functions of the ECM.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536535/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536535/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hynes, Richard O -- P01 HL066105/HL/NHLBI NIH HHS/ -- R01 CA017007/CA/NCI NIH HHS/ -- U54 CA126515/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Nov 27;326(5957):1216-9. doi: 10.1126/science.1176009.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. rohynes@mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19965464" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Adhesion ; *Cell Physiological Processes ; Extracellular Matrix/*physiology ; Extracellular Matrix Proteins/chemistry/*metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Models, Biological ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Structure, Tertiary ; Signal Transduction ; Transforming Growth Factor beta/metabolism
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    Membrane fusion: grappling with SNARE and SM proteins (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-24
    Description: The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion. Vesicular and target membrane-localized SNARE proteins zipper up into an alpha-helical bundle that pulls the two membranes tightly together to exert the force required for fusion. SM proteins, shaped like clasps, bind to trans-SNARE complexes to direct their fusogenic action. Individual fusion reactions are executed by distinct combinations of SNARE and SM proteins to ensure specificity, and are controlled by regulators that embed the SM-SNARE fusion machinery into a physiological context. This regulation is spectacularly apparent in the exquisite speed and precision of synaptic exocytosis, where synaptotagmin (the calcium-ion sensor for fusion) cooperates with complexin (the clamp activator) to control the precisely timed release of neurotransmitters that initiates synaptic transmission and underlies brain function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736821/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736821/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sudhof, Thomas C -- Rothman, James E -- R01 GM071458/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Jan 23;323(5913):474-7. doi: 10.1126/science.1161748.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Physiology, Stanford University, Palo Alto, CA 94304, USA. tcs1@stanford.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19164740" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; *Membrane Fusion ; Munc18 Proteins/chemistry/*metabolism ; Nerve Tissue Proteins/metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Qa-SNARE Proteins/chemistry/metabolism ; SNARE Proteins/chemistry/*metabolism ; Synapses/physiology ; Synaptic Transmission ; Synaptic Vesicles/physiology ; Synaptotagmins/metabolism ; Vesicular Transport Proteins/chemistry/*metabolism
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    Three-dimensional structural view of the central metabolic network of Thermotoga maritima (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-09-19
    Description: Metabolic pathways have traditionally been described in terms of biochemical reactions and metabolites. With the use of structural genomics and systems biology, we generated a three-dimensional reconstruction of the central metabolic network of the bacterium Thermotoga maritima. The network encompassed 478 proteins, of which 120 were determined by experiment and 358 were modeled. Structural analysis revealed that proteins forming the network are dominated by a small number (only 182) of basic shapes (folds) performing diverse but mostly related functions. Most of these folds are already present in the essential core (approximately 30%) of the network, and its expansion by nonessential proteins is achieved with relatively few additional folds. Thus, integration of structural data with networks analysis generates insight into the function, mechanism, and evolution of biological networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833182/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833182/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Ying -- Thiele, Ines -- Weekes, Dana -- Li, Zhanwen -- Jaroszewski, Lukasz -- Ginalski, Krzysztof -- Deacon, Ashley M -- Wooley, John -- Lesley, Scott A -- Wilson, Ian A -- Palsson, Bernhard -- Osterman, Andrei -- Godzik, Adam -- P20 GM076221/GM/NIGMS NIH HHS/ -- P20 GM076221-03/GM/NIGMS NIH HHS/ -- U54 GM074898/GM/NIGMS NIH HHS/ -- U54 GM074898-05/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Sep 18;325(5947):1544-9. doi: 10.1126/science.1174671.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Joint Center for Molecular Modeling (JCMM), Burnham Institute for Medical Research, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19762644" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Computational Biology ; Computer Simulation ; Enzymes/*chemistry/*metabolism ; Evolution, Molecular ; Genes, Bacterial ; Genome, Bacterial ; *Metabolic Networks and Pathways ; Models, Biological ; Models, Molecular ; Protein Conformation ; Protein Folding ; Protein Structure, Tertiary ; Systems Biology ; Thermotoga maritima/chemistry/genetics/*metabolism
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    The tail of integrins, talin, and kindlins (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-05-16
    Description: Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moser, Markus -- Legate, Kyle R -- Zent, Roy -- Fassler, Reinhard -- DK 69921/DK/NIDDK NIH HHS/ -- DK075594/DK/NIDDK NIH HHS/ -- DK65138/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2009 May 15;324(5929):895-9. doi: 10.1126/science.1163865.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19443776" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Adhesion ; Humans ; Integrins/chemistry/*metabolism ; Ligands ; Membrane Proteins/chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Signal Transduction ; Talin/chemistry/*metabolism
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    To nibble at plant resistance proteins (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-05-09
    Description: To intercept invading microbes that threaten growth and reproduction, plants evolved a sophisticated innate immune system. Recognition of specialized pathogens is mediated by resistance proteins that function as molecular switches. Pathogen perception by these multidomain proteins seems to trigger a series of conformational changes dependent on nucleotide exchange. The activated resistance protein switches on host defenses, often culminating in the death of infected cells. Given their control over life and death, activity of these proteins requires tight regulation that involves intramolecular interactions between the various domains.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takken, F L W -- Tameling, W I L -- New York, N.Y. -- Science. 2009 May 8;324(5928):744-6. doi: 10.1126/science.1171666.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plant Pathology, Swammerdam Institute for Life Sciences (SILS), University of Amsterdam, Post Office Box 94215, 1090 GE Amsterdam, the Netherlands. F.L.W.Takken@uva.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19423813" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphatases/chemistry/genetics/*metabolism ; Adenosine Triphosphate/metabolism ; Host-Pathogen Interactions ; Immunity, Innate ; Plant Diseases/*immunology ; Plant Proteins/chemistry/genetics/*metabolism ; Plants/*immunology/metabolism/*microbiology ; Protein Conformation ; Protein Multimerization ; Protein Structure, Tertiary ; Signal Transduction
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    Positive selection of tyrosine loss in metazoan evolution (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-07-11
    Description: John Nash showed that within a complex system, individuals are best off if they make the best decision that they can, taking into account the decisions of the other individuals. Here, we investigate whether similar principles influence the evolution of signaling networks in multicellular animals. Specifically, by analyzing a set of metazoan species we observed a striking negative correlation of genomically encoded tyrosine content with biological complexity (as measured by the number of cell types in each organism). We discuss how this observed tyrosine loss correlates with the expansion of tyrosine kinases in the evolution of the metazoan lineage and how it may relate to the optimization of signaling systems in multicellular animals. We propose that this phenomenon illustrates genome-wide adaptive evolution to accommodate beneficial genetic perturbation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066034/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066034/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tan, Chris Soon Heng -- Pasculescu, Adrian -- Lim, Wendell A -- Pawson, Tony -- Bader, Gary D -- Linding, Rune -- R01 GM055040/GM/NIGMS NIH HHS/ -- R01 GM055040-11/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Sep 25;325(5948):1686-8. doi: 10.1126/science.1174301. Epub 2009 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19589966" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Animals ; *Biological Evolution ; *Evolution, Molecular ; Fungal Proteins/chemistry/metabolism ; Glycosylation ; Humans ; Methylation ; Mutation ; Phosphorylation ; Phosphotyrosine/metabolism ; Protein Structure, Tertiary ; Protein-Tyrosine Kinases/*metabolism ; Proteins/*chemistry/*metabolism ; *Selection, Genetic ; *Signal Transduction ; Substrate Specificity ; Tyrosine/*metabolism
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    The structure of rat liver vault at 3.5 angstrom resolution (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-20
    Description: Vaults are among the largest cytoplasmic ribonucleoprotein particles and are found in numerous eukaryotic species. Roles in multidrug resistance and innate immunity have been suggested, but the cellular function remains unclear. We have determined the x-ray structure of rat liver vault at 3.5 angstrom resolution and show that the cage structure consists of a dimer of half-vaults, with each half-vault comprising 39 identical major vault protein (MVP) chains. Each MVP monomer folds into 12 domains: nine structural repeat domains, a shoulder domain, a cap-helix domain, and a cap-ring domain. Interactions between the 42-turn-long cap-helix domains are key to stabilizing the particle. The shoulder domain is structurally similar to a core domain of stomatin, a lipid-raft component in erythrocytes and epithelial cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanaka, Hideaki -- Kato, Koji -- Yamashita, Eiki -- Sumizawa, Tomoyuki -- Zhou, Yong -- Yao, Min -- Iwasaki, Kenji -- Yoshimura, Masato -- Tsukihara, Tomitake -- New York, N.Y. -- Science. 2009 Jan 16;323(5912):384-8. doi: 10.1126/science.1164975.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19150846" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallization ; Crystallography, X-Ray ; Dimerization ; Liver/*chemistry ; Models, Molecular ; Protein Conformation ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Rats ; Vault Ribonucleoprotein Particles/*chemistry
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    Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-12-19
    Description: Inward-rectifier potassium (K+) channels conduct K+ ions most efficiently in one direction, into the cell. Kir2 channels control the resting membrane voltage in many electrically excitable cells, and heritable mutations cause periodic paralysis and cardiac arrhythmia. We present the crystal structure of Kir2.2 from chicken, which, excluding the unstructured amino and carboxyl termini, is 90% identical to human Kir2.2. Crystals containing rubidium (Rb+), strontium (Sr2+), and europium (Eu3+) reveal binding sites along the ion conduction pathway that are both conductive and inhibitory. The sites correlate with extensive electrophysiological data and provide a structural basis for understanding rectification. The channel's extracellular surface, with large structured turrets and an unusual selectivity filter entryway, might explain the relative insensitivity of eukaryotic inward rectifiers to toxins. These same surface features also suggest a possible approach to the development of inhibitory agents specific to each member of the inward-rectifier K+ channel family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819303/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819303/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tao, Xiao -- Avalos, Jose L -- Chen, Jiayun -- MacKinnon, Roderick -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM043949/GM/NIGMS NIH HHS/ -- R01 GM043949-10/GM/NIGMS NIH HHS/ -- R01 GM043949-11/GM/NIGMS NIH HHS/ -- R01 GM043949-12/GM/NIGMS NIH HHS/ -- R01 GM043949-13/GM/NIGMS NIH HHS/ -- R01 GM043949-14/GM/NIGMS NIH HHS/ -- R01 GM043949-15/GM/NIGMS NIH HHS/ -- R01 GM043949-16/GM/NIGMS NIH HHS/ -- R01 GM043949-17/GM/NIGMS NIH HHS/ -- R01 GM043949-18/GM/NIGMS NIH HHS/ -- R01 GM043949-19/GM/NIGMS NIH HHS/ -- R01 GM043949-20/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Dec 18;326(5960):1668-74. doi: 10.1126/science.1180310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20019282" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Binding Sites ; Chickens ; Cloning, Molecular ; Crystallography, X-Ray ; Europium/metabolism ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Sequence Data ; Oocytes ; Patch-Clamp Techniques ; Potassium/metabolism ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Inwardly Rectifying/antagonists & ; inhibitors/*chemistry/metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry ; Rubidium/metabolism ; Sequence Alignment ; Strontium/metabolism ; Xenopus laevis
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    Cell biology. Evolving cell signals (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collins, Mark O -- New York, N.Y. -- Science. 2009 Sep 25;325(5948):1635-6. doi: 10.1126/science.1180331.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Proteomic Mass Spectrometry Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. moc@sanger.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779182" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; *Biological Evolution ; CDC2 Protein Kinase/antagonists & inhibitors/metabolism ; *Evolution, Molecular ; Fungi/metabolism ; Phosphorylation ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Proteins/*chemistry/*metabolism ; Serine/metabolism ; *Signal Transduction ; Threonine/metabolism ; Tyrosine/metabolism
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    Different T cell receptor signals determine CD8+ memory versus effector development (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-24
    Description: Following infection, naive CD8+ T cells bearing pathogen-specific T cell receptors (TCRs) differentiate into a mixed population of short-lived effector and long-lived memory T cells to mediate an adaptive immune response. How the TCR regulates memory T cell development has remained elusive. Using a mutant TCR transgenic model, we found that point mutations in the TCR beta transmembrane domain (betaTMD) impair the development and function of CD8+ memory T cells without affecting primary effector T cell responses. Mutant T cells are deficient in polarizing the TCR and in organizing the nuclear factor kappaB signal at the immunological synapse. Thus, effector and memory states of CD8+ T cells are separable fates, determined by differential TCR signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teixeiro, Emma -- Daniels, Mark A -- Hamilton, Sara E -- Schrum, Adam G -- Bragado, Rafael -- Jameson, Stephen C -- Palmer, Ed -- New York, N.Y. -- Science. 2009 Jan 23;323(5913):502-5. doi: 10.1126/science.1163612.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Transplantation Immunology, Department of Biomedicine, University Hospital-Basel, Hebelstrasse 20, 4031-Basel, Switzerland. teixeiropernase@missouri.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19164748" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Antigen-Presenting Cells/immunology ; CD8-Positive T-Lymphocytes/cytology/*immunology/metabolism ; Cell Differentiation ; Genes, T-Cell Receptor beta ; Immunization ; *Immunologic Memory ; Immunological Synapses/immunology ; Listeria monocytogenes ; Listeriosis/immunology ; Lymphocyte Count ; Mice ; Mice, Transgenic ; NF-kappa B/*metabolism ; Point Mutation ; Protein Structure, Tertiary ; Receptors, Antigen, T-Cell, alpha-beta/chemistry/genetics/immunology/*metabolism ; *Signal Transduction ; T-Lymphocyte Subsets/cytology/*immunology
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Stretching single talin rod molecules activates vinculin binding (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-31
    Description: The molecular mechanism by which a mechanical stimulus is translated into a chemical response in biological systems is still unclear. We show that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules. We used magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy to investigate the effect of force on the interaction between talin, a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system. Such protein stretching may be a more general mechanism for force transduction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉del Rio, Armando -- Perez-Jimenez, Raul -- Liu, Ruchuan -- Roca-Cusachs, Pere -- Fernandez, Julio M -- Sheetz, Michael P -- New York, N.Y. -- Science. 2009 Jan 30;323(5914):638-41. doi: 10.1126/science.1162912.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Columbia University, New York, NY 10027, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19179532" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Biophysical Phenomena ; Chickens ; Mechanotransduction, Cellular ; Microscopy, Fluorescence ; Models, Molecular ; Photobleaching ; Protein Binding ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/metabolism ; Talin/*chemistry/*metabolism ; Vinculin/*chemistry/*metabolism
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    Solution nuclear magnetic resonance structure of membrane-integral diacylglycerol kinase (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-06-27
    Description: Escherichia coli diacylglycerol kinase (DAGK) represents a family of integral membrane enzymes that is unrelated to all other phosphotransferases. We have determined the three-dimensional structure of the DAGK homotrimer with the use of solution nuclear magnetic resonance. The third transmembrane helix from each subunit is domain-swapped with the first and second transmembrane segments from an adjacent subunit. Each of DAGK's three active sites resembles a portico. The cornice of the portico appears to be the determinant of DAGK's lipid substrate specificity and overhangs the site of phosphoryl transfer near the water-membrane interface. Mutations to cysteine that caused severe misfolding were located in or near the active site, indicating a high degree of overlap between sites responsible for folding and for catalysis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764269/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764269/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Horn, Wade D -- Kim, Hak-Jun -- Ellis, Charles D -- Hadziselimovic, Arina -- Sulistijo, Endah S -- Karra, Murthy D -- Tian, Changlin -- Sonnichsen, Frank D -- Sanders, Charles R -- R01 GM047485/GM/NIGMS NIH HHS/ -- R01 GM047485-17/GM/NIGMS NIH HHS/ -- R01 GM47485/GM/NIGMS NIH HHS/ -- T32 NS007491/NS/NINDS NIH HHS/ -- T32 NS007491-09/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2009 Jun 26;324(5935):1726-9. doi: 10.1126/science.1171716.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19556511" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Biocatalysis ; Catalytic Domain ; Cell Membrane/enzymology ; Diacylglycerol Kinase/*chemistry/metabolism ; Escherichia coli/*enzymology ; Escherichia coli Proteins/*chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Nuclear Magnetic Resonance, Biomolecular ; Protein Conformation ; Protein Folding ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary
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    Cell biology. The force is with us (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwartz, Martin A -- New York, N.Y. -- Science. 2009 Jan 30;323(5914):588-9. doi: 10.1126/science.1169414.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Cardiovascular Research Center and Mellon Urological Cancer Research Institute, University of Virginia, Charlottesville, VA 22908, USA. maschwartz@virginia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19179515" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Cell Adhesion ; Fibronectins/chemistry/*metabolism ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Humans ; Integrin alpha5beta1/chemistry/*metabolism ; *Mechanotransduction, Cellular ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Talin/chemistry/*metabolism ; Vinculin/*metabolism
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    The crystal structure of the ribosome bound to EF-Tu and aminoacyl-tRNA (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-10-17
    Description: The ribosome selects a correct transfer RNA (tRNA) for each amino acid added to the polypeptide chain, as directed by messenger RNA. Aminoacyl-tRNA is delivered to the ribosome by elongation factor Tu (EF-Tu), which hydrolyzes guanosine triphosphate (GTP) and releases tRNA in response to codon recognition. The signaling pathway that leads to GTP hydrolysis upon codon recognition is critical to accurate decoding. Here we present the crystal structure of the ribosome complexed with EF-Tu and aminoacyl-tRNA, refined to 3.6 angstrom resolution. The structure reveals details of the tRNA distortion that allows aminoacyl-tRNA to interact simultaneously with the decoding center of the 30S subunit and EF-Tu at the factor binding site. A series of conformational changes in EF-Tu and aminoacyl-tRNA suggests a communication pathway between the decoding center and the guanosine triphosphatase center of EF-Tu.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763470/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763470/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmeing, T Martin -- Voorhees, Rebecca M -- Kelley, Ann C -- Gao, Yong-Gui -- Murphy, Frank V 4th -- Weir, John R -- Ramakrishnan, V -- 082086/Wellcome Trust/United Kingdom -- MC_U105184332/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2009 Oct 30;326(5953):688-94. doi: 10.1126/science.1179700. Epub 2009 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19833920" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Enzyme Activation ; GTP Phosphohydrolases/metabolism ; Genetic Code ; Models, Molecular ; Nucleic Acid Conformation ; Peptide Elongation Factor Tu/*chemistry ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; RNA, Bacterial/*chemistry ; RNA, Transfer, Amino Acyl/*chemistry ; RNA, Transfer, Phe/chemistry ; RNA, Transfer, Thr/chemistry ; Ribosomes/*chemistry ; Thermus thermophilus
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    Structure of an RNA polymerase II-TFIIB complex and the transcription initiation mechanism (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-12-08
    Description: Previous x-ray crystal structures have given insight into the mechanism of transcription and the role of general transcription factors in the initiation of the process. A structure of an RNA polymerase II-general transcription factor TFIIB complex at 4.5 angstrom resolution revealed the amino-terminal region of TFIIB, including a loop termed the "B finger," reaching into the active center of the polymerase where it may interact with both DNA and RNA, but this structure showed little of the carboxyl-terminal region. A new crystal structure of the same complex at 3.8 angstrom resolution obtained under different solution conditions is complementary with the previous one, revealing the carboxyl-terminal region of TFIIB, located above the polymerase active center cleft, but showing none of the B finger. In the new structure, the linker between the amino- and carboxyl-terminal regions can also be seen, snaking down from above the cleft toward the active center. The two structures, taken together with others previously obtained, dispel long-standing mysteries of the transcription initiation process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813267/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813267/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Xin -- Bushnell, David A -- Wang, Dong -- Calero, Guillermo -- Kornberg, Roger D -- AI21144/AI/NIAID NIH HHS/ -- GM049985/GM/NIGMS NIH HHS/ -- K99 GM085136/GM/NIGMS NIH HHS/ -- K99 GM085136-02/GM/NIGMS NIH HHS/ -- R00 GM085136/GM/NIGMS NIH HHS/ -- R01 AI021144/AI/NIAID NIH HHS/ -- R01 AI021144-25/AI/NIAID NIH HHS/ -- R01 GM036659/GM/NIGMS NIH HHS/ -- R01 GM049985/GM/NIGMS NIH HHS/ -- R01 GM049985-16/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2010 Jan 8;327(5962):206-9. doi: 10.1126/science.1182015. Epub 2009 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19965383" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Structure, Secondary ; Protein Structure, Tertiary ; RNA Polymerase II/*chemistry/*metabolism ; Repetitive Sequences, Amino Acid ; Saccharomyces cerevisiae/chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Transcription Factor TFIIB/*chemistry/*metabolism ; *Transcription, Genetic
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    Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1 (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-08-08
    Description: Posttranslational modifications play key roles in regulating chromatin plasticity. Although various chromatin-remodeling enzymes have been described that respond to specific histone modifications, little is known about the role of poly[adenosine 5'-diphosphate (ADP)-ribose] in chromatin remodeling. Here, we identify a chromatin-remodeling enzyme, ALC1 (Amplified in Liver Cancer 1, also known as CHD1L), that interacts with poly(ADP-ribose) and catalyzes PARP1-stimulated nucleosome sliding. Our results define ALC1 as a DNA damage-response protein whose role in this process is sustained by its association with known DNA repair factors and its rapid poly(ADP-ribose)-dependent recruitment to DNA damage sites. Furthermore, we show that depletion or overexpression of ALC1 results in sensitivity to DNA-damaging agents. Collectively, these results provide new insights into the mechanisms by which poly(ADP-ribose) regulates DNA repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443743/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443743/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahel, Dragana -- Horejsi, Zuzana -- Wiechens, Nicola -- Polo, Sophie E -- Garcia-Wilson, Elisa -- Ahel, Ivan -- Flynn, Helen -- Skehel, Mark -- West, Stephen C -- Jackson, Stephen P -- Owen-Hughes, Tom -- Boulton, Simon J -- 064414/Wellcome Trust/United Kingdom -- 11224/Cancer Research UK/United Kingdom -- A3549/Cancer Research UK/United Kingdom -- A5290/Cancer Research UK/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Department of Health/United Kingdom -- New York, N.Y. -- Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DNA Damage Response Laboratory, Clare Hall, London Research Institute, South Mimms EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19661379" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Cell Line ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; DNA Damage ; DNA Helicases/chemistry/genetics/*metabolism ; *DNA Repair ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Immunoprecipitation ; Kinetics ; Mutant Proteins/chemistry/metabolism ; Nucleosomes/metabolism ; Phleomycins/pharmacology ; Poly Adenosine Diphosphate Ribose/*metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Structure, Tertiary ; Radiation, Ionizing ; Recombinant Proteins/chemistry/metabolism
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    Plant science. Anti-rust antitrust (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kliebenstein, Daniel J -- Rowe, Heather C -- New York, N.Y. -- Science. 2009 Mar 6;323(5919):1301-2. doi: 10.1126/science.1171410.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Sciences and Genetics Graduate Group, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA. kliebenstein@ucdavis.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19265010" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry/genetics/metabolism ; Ascomycota/genetics/*pathogenicity ; Basidiomycota/genetics/*pathogenicity ; Cloning, Molecular ; Evolution, Molecular ; *Genes, Plant ; Immunity, Innate ; Phosphotransferases/chemistry/genetics/metabolism ; *Plant Diseases/immunology/microbiology ; Plant Proteins/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; *Quantitative Trait Loci ; Selection, Genetic ; Triticum/genetics/*microbiology
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    RSY-1 is a local inhibitor of presynaptic assembly in C. elegans (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-17
    Description: As fundamental units of neuronal communication, chemical synapses are composed of presynaptic and postsynaptic specializations that form at specific locations with defined shape and size. Synaptic assembly must be tightly regulated to prevent overgrowth of the synapse size and number, but the molecular mechanisms that inhibit synapse assembly are poorly understood. We identified regulator of synaptogenesis-1 (RSY-1) as an evolutionarily conserved molecule that locally antagonized presynaptic assembly. The loss of RSY-1 in Caenorhabditis elegans led to formation of extra synapses and recruitment of excessive synaptic material to presynaptic sites. RSY-1 directly interacted with and negatively regulated SYD-2/liprin-alpha, a master assembly molecule that recruits numerous synaptic components to presynaptic sites. RSY-1 also bound and regulated SYD-1, a synaptic protein required for proper functioning of SYD-2. Thus, local inhibitory mechanisms govern synapse formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087376/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087376/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Patel, Maulik R -- Shen, Kang -- 1R01NS048392/NS/NINDS NIH HHS/ -- R01 NS048392/NS/NINDS NIH HHS/ -- R01 NS048392-05/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Mar 13;323(5920):1500-3. doi: 10.1126/science.1169025.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neurosciences Program, Stanford University, 385 Serra Mall, Herrin Labs, Room 144, Stanford University, Stanford,CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19286562" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/genetics/*physiology ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Carrier Proteins/metabolism ; Cell Line ; Cell Nucleus/metabolism ; Humans ; Mutation ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism ; Phosphoproteins/genetics/metabolism ; Protein Binding ; Protein Interaction Mapping ; Protein Isoforms/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/metabolism ; Synapses/metabolism/*physiology
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    PAN1: a receptor-like protein that promotes polarization of an asymmetric cell division in maize (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-31
    Description: Polarization of cell division is essential for eukaryotic development, but little is known about how this is accomplished in plants. The formation of stomatal complexes in maize involves the polarization of asymmetric subsidiary mother cell (SMC) divisions toward the adjacent guard mother cell (GMC), apparently under the influence of a GMC-derived signal. We found that the maize pan1 gene promotes the premitotic polarization of SMCs and encodes a leucine-rich repeat receptor-like protein that becomes localized in SMCs at sites of GMC contact. PAN1 has an inactive kinase domain but is required for the accumulation of a membrane-associated phosphoprotein, suggesting a function for PAN1 in signal transduction. Our findings implicate PAN1 in the transmission of an extrinsic signal that polarizes asymmetric SMC divisions toward GMCs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cartwright, Heather N -- Humphries, John A -- Smith, Laurie G -- New York, N.Y. -- Science. 2009 Jan 30;323(5914):649-51. doi: 10.1126/science.1161686.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Cell and Developmental Biology, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093-0116, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19179535" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Amino Acid Sequence ; Cell Division ; Cell Nucleus/ultrastructure ; Cell Polarity ; Cues ; Genes, Plant ; Molecular Sequence Data ; Phosphorylation ; Plant Leaves/*cytology ; Plant Proteins/chemistry/genetics/*metabolism ; Plant Stomata/*cytology/genetics/growth & development/metabolism ; Protein Structure, Tertiary ; Signal Transduction ; Zea mays/*cytology/genetics/growth & development/metabolism
    Print ISSN: 0036-8075
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    Antibody recognition of a highly conserved influenza virus epitope (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-03
    Description: Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758658/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758658/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ekiert, Damian C -- Bhabha, Gira -- Elsliger, Marc-Andre -- Friesen, Robert H E -- Jongeneelen, Mandy -- Throsby, Mark -- Goudsmit, Jaap -- Wilson, Ian A -- AI-058113/AI/NIAID NIH HHS/ -- P01 AI058113/AI/NIAID NIH HHS/ -- P01 AI058113-040002/AI/NIAID NIH HHS/ -- U54 GM074898/GM/NIGMS NIH HHS/ -- U54 GM074898-03/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Apr 10;324(5924):246-51. doi: 10.1126/science.1171491. Epub 2009 Feb 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19251591" target="_blank"〉PubMed〈/a〉
    Keywords: Antibodies, Viral/chemistry/*immunology ; *Antibody Affinity ; Antigens, Viral/chemistry/*immunology ; *Binding Sites, Antibody ; Crystallization ; Crystallography, X-Ray ; Epitopes/immunology ; Glycosylation ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry/*immunology ; Humans ; Hydrogen Bonding ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Immunoglobulin Fab Fragments/chemistry/*immunology ; Influenza A Virus, H1N1 Subtype/*immunology ; Influenza A Virus, H5N1 Subtype/*immunology ; Influenza Vaccines ; Membrane Fusion ; Models, Molecular ; Neutralization Tests ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary
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    Activation of Rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-12
    Description: Activation of Rho guanosine triphosphatases (GTPases) to the guanine triphosphate (GTP)-bound state is a critical event in their regulation of the cytoskeleton and cell signaling. Members of the DOCK family of guanine nucleotide exchange factors (GEFs) are important activators of Rho GTPases, but the mechanism of activation by their catalytic DHR2 domain is unknown. Through structural analysis of DOCK9-Cdc42 complexes, we identify a nucleotide sensor within the alpha10 helix of the DHR2 domain that contributes to release of guanine diphosphate (GDP) and then to discharge of the activated GTP-bound Cdc42. Magnesium exclusion, a critical factor in promoting GDP release, is mediated by a conserved valine residue within this sensor, whereas binding of GTP-Mg2+ to the nucleotide-free complex results in magnesium-inducing displacement of the sensor to stimulate discharge of Cdc42-GTP. These studies identify an unusual mechanism of GDP release and define the complete GEF catalytic cycle from GDP dissociation followed by GTP binding and discharge of the activated GTPase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Jing -- Zhang, Ziguo -- Roe, S Mark -- Marshall, Christopher J -- Barford, David -- 10433/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2009 Sep 11;325(5946):1398-402. doi: 10.1126/science.1174468.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19745154" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation ; Guanine Nucleotide Exchange Factors/*chemistry/*metabolism ; Guanosine Diphosphate/*metabolism ; Guanosine Triphosphate/*metabolism ; Humans ; Magnesium/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; cdc42 GTP-Binding Protein/*chemistry/*metabolism
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    Sending signals dynamically (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-04-11
    Description: Proteins mediate transmission of signals along intercellular and intracellular pathways and between the exterior and the interior of a cell. The dynamic properties of signaling proteins are crucial to their functions. We discuss emerging paradigms for the role of protein dynamics in signaling. A central tenet is that proteins fluctuate among many states on evolutionarily selected energy landscapes. Upstream signals remodel this landscape, causing signaling proteins to transmit information to downstream partners. New methods provide insight into the dynamic properties of signaling proteins at the atomic scale. The next stages in the signaling hierarchy-how multiple signals are integrated and how cellular signaling pathways are organized in space and time-present exciting challenges for the future, requiring bold multidisciplinary approaches.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921701/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921701/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smock, Robert G -- Gierasch, Lila M -- DP1 OD000945/OD/NIH HHS/ -- DP1 OD000945-03/OD/NIH HHS/ -- GM027616/GM/NIGMS NIH HHS/ -- OD000945/OD/NIH HHS/ -- R01 GM027616/GM/NIGMS NIH HHS/ -- R01 GM027616-30/GM/NIGMS NIH HHS/ -- T32 GM008515/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Apr 10;324(5924):198-203. doi: 10.1126/science.1169377.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA. rsmock@student.umass.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19359576" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Intercellular Signaling Peptides and Proteins/*chemistry/*metabolism ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/*chemistry/*metabolism ; Models, Molecular ; Motion ; PDZ Domains ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Structure, Tertiary ; *Signal Transduction ; Thermodynamics
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    McsB is a protein arginine kinase that phosphorylates and inhibits the heat-shock regulator CtsR (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-06-06
    Description: All living organisms face a variety of environmental stresses that cause the misfolding and aggregation of proteins. To eliminate damaged proteins, cells developed highly efficient stress response and protein quality control systems. We performed a biochemical and structural analysis of the bacterial CtsR/McsB stress response. The crystal structure of the CtsR repressor, in complex with DNA, pinpointed key residues important for high-affinity binding to the promoter regions of heat-shock genes. Moreover, biochemical characterization of McsB revealed that McsB specifically phosphorylates arginine residues in the DNA binding domain of CtsR, thereby impairing its function as a repressor of stress response genes. Identification of the CtsR/McsB arginine phospho-switch expands the repertoire of possible protein modifications involved in prokaryotic and eukaryotic transcriptional regulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fuhrmann, Jakob -- Schmidt, Andreas -- Spiess, Silvia -- Lehner, Anita -- Turgay, Kursad -- Mechtler, Karl -- Charpentier, Emmanuelle -- Clausen, Tim -- New York, N.Y. -- Science. 2009 Jun 5;324(5932):1323-7. doi: 10.1126/science.1170088.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19498169" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arginine/metabolism ; Bacterial Proteins/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Crystallography, X-Ray ; DNA, Bacterial/metabolism ; Electrophoretic Mobility Shift Assay ; Gene Expression Regulation, Bacterial ; Geobacillus stearothermophilus/genetics/*metabolism ; Heat-Shock Response/*genetics ; Helix-Turn-Helix Motifs ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Phosphorylation ; Promoter Regions, Genetic ; Protein Kinases/chemistry/genetics/*metabolism ; Protein Structure, Tertiary ; Repressor Proteins/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Tandem Mass Spectrometry
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    Lysine acetylation targets protein complexes and co-regulates major cellular functions (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-07-18
    Description: Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choudhary, Chunaram -- Kumar, Chanchal -- Gnad, Florian -- Nielsen, Michael L -- Rehman, Michael -- Walther, Tobias C -- Olsen, Jesper V -- Mann, Matthias -- New York, N.Y. -- Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19608861" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Amino Acid Motifs ; Benzamides/pharmacology ; Cell Line, Tumor ; Cell Nucleus/metabolism ; *Cell Physiological Phenomena ; Cytoplasm/metabolism ; Enzyme Inhibitors/pharmacology ; Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Lysine/*metabolism ; Mass Spectrometry ; Metabolic Networks and Pathways ; Mitochondria/metabolism ; Multiprotein Complexes/chemistry/*metabolism ; *Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Proteins/chemistry/*metabolism ; Proteome/*analysis ; Proteomics ; Pyridines/pharmacology ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism
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    Loss of function of a proline-containing protein confers durable disease resistance in rice (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-08-22
    Description: Blast disease is a devastating fungal disease of rice, one of the world's staple foods. Race-specific resistance to blast disease has usually not been durable. Here, we report the cloning of a previously unknown type of gene that confers non-race-specific resistance and its successful use in breeding. Pi21 encodes a proline-rich protein that includes a putative heavy metal-binding domain and putative protein-protein interaction motifs. Wild-type Pi21 appears to slow the plant's defense responses, which may support optimization of defense mechanisms. Deletions in its proline-rich motif inhibit this slowing. Pi21 is separable from a closely linked gene conferring poor flavor. The resistant pi21 allele, which is found in some strains of japonica rice, could improve blast resistance of rice worldwide.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fukuoka, Shuichi -- Saka, Norikuni -- Koga, Hironori -- Ono, Kazuko -- Shimizu, Takehiko -- Ebana, Kaworu -- Hayashi, Nagao -- Takahashi, Akira -- Hirochika, Hirohiko -- Okuno, Kazutoshi -- Yano, Masahiro -- New York, N.Y. -- Science. 2009 Aug 21;325(5943):998-1001. doi: 10.1126/science.1175550.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉QTL Genomics Research Center, National Institute of Agrobiological Sciences, Kannondai 2-1-2, Tsukuba, Ibaraki 305-8602, Japan. fukusan@affrc.go.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19696351" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Motifs ; Amino Acid Sequence ; Chromosome Mapping ; Cloning, Molecular ; Genes, Plant ; Genetic Variation ; Haplotypes ; Immunity, Innate/*genetics ; Magnaporthe/*pathogenicity ; Molecular Sequence Data ; Oryza/*genetics/metabolism/*microbiology ; Phylogeny ; Plant Diseases/*microbiology ; Plant Proteins/chemistry/*genetics/*physiology ; Proline/analysis ; Protein Interaction Domains and Motifs ; Protein Structure, Tertiary ; Quantitative Trait Loci ; Sequence Deletion ; Transformation, Genetic
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    Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-05
    Description: PTEN (phosphatase and tensin homolog on chromosome 10) is a tumor suppressor whose cellular regulation remains incompletely understood. We identified phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) as a PTEN-interacting protein. P-REX2a mRNA was more abundant in human cancer cells and significantly increased in tumors with wild-type PTEN that expressed an activated mutant of PIK3CA encoding the p110 subunit of phosphoinositide 3-kinase subunit alpha (PI3Kalpha). P-REX2a inhibited PTEN lipid phosphatase activity and stimulated the PI3K pathway only in the presence of PTEN. P-REX2a stimulated cell growth and cooperated with a PIK3CA mutant to promote growth factor-independent proliferation and transformation. Depletion of P-REX2a reduced amounts of phosphorylated AKT and growth in human cell lines with intact PTEN. Thus, P-REX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936784/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936784/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fine, Barry -- Hodakoski, Cindy -- Koujak, Susan -- Su, Tao -- Saal, Lao H -- Maurer, Matthew -- Hopkins, Benjamin -- Keniry, Megan -- Sulis, Maria Luisa -- Mense, Sarah -- Hibshoosh, Hanina -- Parsons, Ramon -- CA097403/CA/NCI NIH HHS/ -- P01 CA097403/CA/NCI NIH HHS/ -- P01 CA097403-01A10003/CA/NCI NIH HHS/ -- P01 CA097403-06A1/CA/NCI NIH HHS/ -- R01 CA082783/CA/NCI NIH HHS/ -- R01 CA082783-06/CA/NCI NIH HHS/ -- R01 CA082783-07/CA/NCI NIH HHS/ -- R01 CA082783-08/CA/NCI NIH HHS/ -- R01 CA082783-09/CA/NCI NIH HHS/ -- R01 CA082783-10/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Sep 4;325(5945):1261-5. doi: 10.1126/science.1173569.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19729658" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/genetics/metabolism/pathology ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Female ; GTPase-Activating Proteins/genetics/*metabolism ; Guanine Nucleotide Exchange Factors ; Humans ; Male ; Mutation ; Neoplasms/genetics/*metabolism/pathology ; PTEN Phosphohydrolase/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
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    Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-28
    Description: Protein folding in the endoplasmic reticulum is a complex process whose malfunction is implicated in disease and aging. By using the cell's endogenous sensor (the unfolded protein response), we identified several hundred yeast genes with roles in endoplasmic reticulum folding and systematically characterized their functional interdependencies by measuring unfolded protein response levels in double mutants. This strategy revealed multiple conserved factors critical for endoplasmic reticulum folding, including an intimate dependence on the later secretory pathway, a previously uncharacterized six-protein transmembrane complex, and a co-chaperone complex that delivers tail-anchored proteins to their membrane insertion machinery. The use of a quantitative reporter in a comprehensive screen followed by systematic analysis of genetic dependencies should be broadly applicable to functional dissection of complex cellular processes from yeast to human.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877488/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877488/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jonikas, Martin C -- Collins, Sean R -- Denic, Vladimir -- Oh, Eugene -- Quan, Erin M -- Schmid, Volker -- Weibezahn, Jimena -- Schwappach, Blanche -- Walter, Peter -- Weissman, Jonathan S -- Schuldiner, Maya -- 081671/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Mar 27;323(5922):1693-7. doi: 10.1126/science.1167983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325107" target="_blank"〉PubMed〈/a〉
    Keywords: Endoplasmic Reticulum/*metabolism ; Epistasis, Genetic ; Gene Deletion ; Gene Expression Regulation, Fungal ; *Genes, Fungal ; Genes, Reporter ; Membrane Proteins/chemistry/genetics/metabolism ; Mutation ; Phenotype ; *Protein Folding ; *Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/metabolism ; Secretory Pathway
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    Crystal structure of the nuclear export receptor CRM1 in complex with Snurportin1 and RanGTP (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-04-25
    Description: CRM1 mediates nuclear export of numerous unrelated cargoes, which may carry a short leucine-rich nuclear export signal or export signatures that include folded domains. How CRM1 recognizes such a variety of cargoes has been unknown up to this point. Here we present the crystal structure of the SPN1.CRM1.RanGTP export complex at 2.5 angstrom resolution (where SPN1 is snurportin1 and RanGTP is guanosine 5' triphosphate-bound Ran). SPN1 is a nuclear import adapter for cytoplasmically assembled, m(3)G-capped spliceosomal U snRNPs (small nuclear ribonucleoproteins). The structure shows how CRM1 can specifically return the cargo-free form of SPN1 to the cytoplasm. The extensive contact area includes five hydrophobic residues at the SPN1 amino terminus that dock into a hydrophobic cleft of CRM1, as well as numerous hydrophilic contacts of CRM1 to m(3)G cap-binding domain and carboxyl-terminal residues of SPN1. The structure suggests that RanGTP promotes cargo-binding to CRM1 solely through long-range conformational changes in the exportin.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Monecke, Thomas -- Guttler, Thomas -- Neumann, Piotr -- Dickmanns, Achim -- Gorlich, Dirk -- Ficner, Ralf -- New York, N.Y. -- Science. 2009 May 22;324(5930):1087-91. doi: 10.1126/science.1173388. Epub 2009 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Abteilung fur Molekulare Strukturbiologie, Institut fur Mikrobiologie und Genetik, GZMB, Georg-August-Universitat Gottingen, Justus-von-Liebig-Weg 11, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19389996" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Guanosine Triphosphate/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Karyopherins/*chemistry/metabolism ; Mice ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; RNA Cap-Binding Proteins/*chemistry/metabolism ; Receptors, Cytoplasmic and Nuclear/*chemistry/metabolism ; beta Karyopherins/metabolism ; ran GTP-Binding Protein/*chemistry/metabolism
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  • 86
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    Ligand-dependent equilibrium fluctuations of single calmodulin molecules (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-31
    Description: Single-molecule force spectroscopy allows superb mechanical control of protein conformation. We used a custom-built low-drift atomic force microscope to observe mechanically induced conformational equilibrium fluctuations of single molecules of the eukaryotic calcium-dependent signal transducer calmodulin (CaM). From this data, the ligand dependence of the full energy landscape can be reconstructed. We find that calcium ions affect the folding kinetics of the individual CaM domains, whereas target peptides stabilize the already folded structure. Single-molecule data of full length CaM reveal that a wasp venom peptide binds noncooperatively to CaM with 2:1 stoichiometry, whereas a target enzyme peptide binds cooperatively with 1:1 stoichiometry. If mechanical load is applied directly to the target peptide, real-time binding/unbinding transitions can be observed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Junker, Jan Philipp -- Ziegler, Fabian -- Rief, Matthias -- New York, N.Y. -- Science. 2009 Jan 30;323(5914):633-7. doi: 10.1126/science.1166191.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Physik Department E22, Technische Universitat Munchen, James-Franck-Strasse, 85748 Munchen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19179531" target="_blank"〉PubMed〈/a〉
    Keywords: Calcium/*metabolism ; Calmodulin/*chemistry/*metabolism ; Humans ; Kinetics ; Ligands ; Microscopy, Atomic Force ; Monte Carlo Method ; Myosin-Light-Chain Kinase/chemistry/*metabolism ; Peptide Fragments/chemistry/metabolism ; Peptides/chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Protein Folding ; Protein Structure, Tertiary ; Thermodynamics ; Wasp Venoms/chemistry/*metabolism
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  • 87
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    Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-06-06
    Description: Von Willebrand factor (VWF) is secreted as ultralarge multimers that are cleaved in the A2 domain by the metalloprotease ADAMTS13 to give smaller multimers. Cleaved VWF is activated by hydrodynamic forces found in arteriolar bleeding to promote hemostasis, whereas uncleaved VWF is activated at lower, physiologic shear stresses and causes thrombosis. Single-molecule experiments demonstrate that elongational forces in the range experienced by VWF in the vasculature unfold the A2 domain, and only the unfolded A2 domain is cleaved by ADAMTS13. In shear flow, tensile force on a VWF multimer increases with the square of multimer length and is highest at the middle, providing an efficient mechanism for homeostatic regulation of VWF size distribution by force-induced A2 unfolding and cleavage by ADAMTS13, as well as providing a counterbalance for VWF-mediated platelet aggregation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753189/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753189/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xiaohui -- Halvorsen, Kenneth -- Zhang, Cheng-Zhong -- Wong, Wesley P -- Springer, Timothy A -- HL-48675/HL/NHLBI NIH HHS/ -- P01 HL048675/HL/NHLBI NIH HHS/ -- P01 HL048675-16/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2009 Jun 5;324(5932):1330-4. doi: 10.1126/science.1170905.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19498171" target="_blank"〉PubMed〈/a〉
    Keywords: ADAM Proteins/*metabolism ; Binding Sites ; Blood Coagulation/physiology ; *Hemostasis ; Humans ; Kinetics ; *Mechanical Phenomena ; Optical Tweezers ; Platelet Aggregation ; Protein Conformation ; Protein Folding ; Protein Multimerization ; Protein Structure, Tertiary ; Stress, Mechanical ; Thermodynamics ; von Willebrand Factor/*chemistry/*metabolism
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  • 88
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    Cytosolic viral sensor RIG-I is a 5'-triphosphate-dependent translocase on double-stranded RNA (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-03
    Description: Retinoic acid inducible-gene I (RIG-I) is a cytosolic multidomain protein that detects viral RNA and elicits an antiviral immune response. Two N-terminal caspase activation and recruitment domains (CARDs) transmit the signal, and the regulatory domain prevents signaling in the absence of viral RNA. 5'-triphosphate and double-stranded RNA (dsRNA) are two molecular patterns that enable RIG-I to discriminate pathogenic from self-RNA. However, the function of the DExH box helicase domain that is also required for activity is less clear. Using single-molecule protein-induced fluorescence enhancement, we discovered a robust adenosine 5'-triphosphate-powered dsRNA translocation activity of RIG-I. The CARDs dramatically suppress translocation in the absence of 5'-triphosphate, and the activation by 5'-triphosphate triggers RIG-I to translocate preferentially on dsRNA in cis. This functional integration of two RNA molecular patterns may provide a means to specifically sense and counteract replicating viruses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567915/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567915/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Myong, Sua -- Cui, Sheng -- Cornish, Peter V -- Kirchhofer, Axel -- Gack, Michaela U -- Jung, Jae U -- Hopfner, Karl-Peter -- Ha, Taekjip -- CA82057/CA/NCI NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- R01-GM065367/GM/NIGMS NIH HHS/ -- U19 AI083025/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Feb 20;323(5917):1070-4. doi: 10.1126/science.1168352. Epub 2009 Jan 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Champaign, IL 61801, USA. smyong@uiuc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19119185" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/*metabolism ; Animals ; Cell Line ; Cytosol/metabolism ; DEAD-box RNA Helicases/chemistry/genetics/*metabolism ; Kinetics ; Nucleic Acid Heteroduplexes ; Protein Structure, Tertiary ; RNA/metabolism ; RNA, Double-Stranded/*metabolism ; RNA, Viral/metabolism ; Receptors, Pattern Recognition/chemistry/genetics/*metabolism ; Signal Transduction ; Temperature
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    The C-Ala domain brings together editing and aminoacylation functions on one tRNA (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-08-08
    Description: Protein synthesis involves the accurate attachment of amino acids to their matching transfer RNA (tRNA) molecules. Mistranslating the amino acids serine or glycine for alanine is prevented by the function of independent but collaborative aminoacylation and editing domains of alanyl-tRNA synthetases (AlaRSs). We show that the C-Ala domain plays a key role in AlaRS function. The C-Ala domain is universally tethered to the editing domain both in AlaRS and in many homologous free-standing editing proteins. Crystal structure and functional analyses showed that C-Ala forms an ancient single-stranded nucleic acid binding motif that promotes cooperative binding of both aminoacylation and editing domains to tRNA(Ala). In addition, C-Ala may have played an essential role in the evolution of AlaRSs by coupling aminoacylation to editing to prevent mistranslation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559334/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559334/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Min -- Chong, Yeeting E -- Beebe, Kirk -- Shapiro, Ryan -- Yang, Xiang-Lei -- Schimmel, Paul -- GM 15539/GM/NIGMS NIH HHS/ -- R01 GM015539/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Aug 7;325(5941):744-7. doi: 10.1126/science.1174343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19661429" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine-tRNA Ligase/*chemistry/*metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Bacteria/enzymology ; Base Sequence ; Crystallography, X-Ray ; Escherichia coli Proteins/chemistry/metabolism ; Evolution, Molecular ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Phylogeny ; Protein Structure, Secondary ; Protein Structure, Tertiary ; RNA, Bacterial/chemistry/metabolism ; RNA, Transfer, Ala/*chemistry/*metabolism ; RNA, Transfer, Amino Acyl/chemistry/metabolism ; *Transfer RNA Aminoacylation
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  • 90
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    Host inhibition of a bacterial virulence effector triggers immunity to infection (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-05-09
    Description: Plant pathogenic bacteria secrete effector proteins that attack the host signaling machinery to suppress immunity. Effectors can be recognized by hosts leading to immunity. One such effector is AvrPtoB of Pseudomonas syringae, which degrades host protein kinases, such as tomato Fen, through an E3 ligase domain. Pto kinase, which is highly related to Fen, recognizes AvrPtoB in conjunction with the resistance protein Prf. Here we show that Pto is resistant to AvrPtoB-mediated degradation because it inactivates the E3 ligase domain. AvrPtoB ubiquitinated Fen within the catalytic cleft, leading to its breakdown and loss of the associated Prf protein. Pto avoids this by phosphorylating and inactivating the AvrPtoB E3 domain. Thus, inactivation of a pathogen virulence molecule is one mechanism by which plants resist disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ntoukakis, Vardis -- Mucyn, Tatiana S -- Gimenez-Ibanez, Selena -- Chapman, Helen C -- Gutierrez, Jose R -- Balmuth, Alexi L -- Jones, Alexandra M E -- Rathjen, John P -- BB/D00456X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2009 May 8;324(5928):784-7. doi: 10.1126/science.1169430.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sainsbury Laboratory, Colney, Norwich NR4 7UH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19423826" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism ; Immunity, Innate ; Lycopersicon esculentum/genetics/*metabolism/*microbiology ; Mutant Proteins/metabolism ; Phosphorylation ; Plant Diseases/immunology/*microbiology ; Plant Leaves/metabolism ; Plant Proteins/*metabolism ; Plants, Genetically Modified ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*metabolism ; Pseudomonas syringae/genetics/growth & development/metabolism/*pathogenicity ; Signal Transduction ; Tobacco/genetics/metabolism/microbiology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Virulence Factors/antagonists & inhibitors/metabolism
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    Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-03-21
    Description: The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site that binds two distinct proteins with high affinity. We isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the two antigens. An affinity-improved version of bH1 inhibits both HER2- and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. Such "two-in-one" antibodies challenge the monoclonal antibody paradigm of one binding site, one antigen. They could also provide new opportunities for antibody-based therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bostrom, Jenny -- Yu, Shang-Fan -- Kan, David -- Appleton, Brent A -- Lee, Chingwei V -- Billeci, Karen -- Man, Wenyan -- Peale, Franklin -- Ross, Sarajane -- Wiesmann, Christian -- Fuh, Germaine -- New York, N.Y. -- Science. 2009 Mar 20;323(5921):1610-4. doi: 10.1126/science.1165480.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Protein Engineering, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19299620" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Bispecific/chemistry/genetics/*immunology/therapeutic use ; Antibodies, Monoclonal/chemistry/genetics/*immunology/therapeutic use ; Antibodies, Monoclonal, Humanized ; Antibody Affinity ; Antibody Specificity ; Binding Sites, Antibody/genetics ; Cell Proliferation/drug effects ; Complementarity Determining Regions/genetics/immunology ; Crystallography, X-Ray ; Epitopes/immunology/metabolism ; Genetic Engineering ; Humans ; Mice ; Models, Molecular ; Mutagenesis ; Neoplasms, Experimental/drug therapy ; Protein Conformation ; Protein Structure, Tertiary ; Receptor, ErbB-2/chemistry/*immunology/metabolism ; Thermodynamics ; Trastuzumab ; Vascular Endothelial Growth Factor A/chemistry/*immunology/metabolism ; Xenograft Model Antitumor Assays
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  • 92
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    Crystal structure of a nucleocapsid-like nucleoprotein-RNA complex of respiratory syncytial virus (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-12-08
    Description: The respiratory syncytial virus (RSV) is an important human pathogen, yet neither a vaccine nor effective therapies are available to treat infection. To help elucidate the replication mechanism of this RNA virus, we determined the three-dimensional (3D) crystal structure at 3.3 A resolution of a decameric, annular ribonucleoprotein complex of the RSV nucleoprotein (N) bound to RNA. This complex mimics one turn of the viral helical nucleocapsid complex, which serves as template for viral RNA synthesis. The RNA wraps around the protein ring, with seven nucleotides contacting each N subunit, alternating rows of four and three stacked bases that are exposed and buried within a protein groove, respectively. Combined with electron microscopy data, this structure provides a detailed model for the RSV nucleocapsid, in which the bases are accessible for readout by the viral polymerase. Furthermore, the nucleoprotein structure highlights possible key sites for drug targeting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tawar, Rajiv G -- Duquerroy, Stephane -- Vonrhein, Clemens -- Varela, Paloma F -- Damier-Piolle, Laurence -- Castagne, Nathalie -- MacLellan, Kirsty -- Bedouelle, Hugues -- Bricogne, Gerard -- Bhella, David -- Eleouet, Jean-Francois -- Rey, Felix A -- New York, N.Y. -- Science. 2009 Nov 27;326(5957):1279-83. doi: 10.1126/science.1177634.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Unite de Virologie Structurale, Departement de Virologie and CNRS Unite de Recherche Associee (URA) 3015, 25 Rue du Dr Roux, 75724 Paris Cedex 15, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19965480" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Image Processing, Computer-Assisted ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleocapsid Proteins/*chemistry/metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA, Viral/*chemistry/metabolism ; Respiratory Syncytial Viruses/*chemistry/metabolism
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    The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-02-14
    Description: Deposition of the amyloid-beta peptide is a pathological hallmark of Alzheimer's disease. A high-throughput functional genomics screen identified G protein-coupled receptor 3 (GPR3), a constitutively active orphan G protein-coupled receptor, as a modulator of amyloid-beta production. Overexpression of GPR3 stimulated amyloid-beta production, whereas genetic ablation of GPR3 prevented accumulation of the amyloid-beta peptide in vitro and in an Alzheimer's disease mouse model. GPR3 expression led to increased formation and cell-surface localization of the mature gamma-secretase complex in the absence of an effect on Notch processing. GPR3 is highly expressed in areas of the normal human brain implicated in Alzheimer's disease and is elevated in the sporadic Alzheimer's disease brain. Thus, GPR3 represents a potential therapeutic target for the treatment of Alzheimer's disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thathiah, Amantha -- Spittaels, Kurt -- Hoffmann, Marcel -- Staes, Mik -- Cohen, Adrian -- Horre, Katrien -- Vanbrabant, Mieke -- Coun, Frea -- Baekelandt, Veerle -- Delacourte, Andre -- Fischer, David F -- Pollet, Dirk -- De Strooper, Bart -- Merchiers, Pascal -- New York, N.Y. -- Science. 2009 Feb 13;323(5916):946-51. doi: 10.1126/science.1160649.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Developmental Genetics, Vlaams Institute for Biotechnology, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19213921" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/*biosynthesis ; Animals ; Cell Line ; Cell Line, Tumor ; Cells, Cultured ; Female ; Humans ; Male ; Mice ; Middle Aged ; Neurons/*metabolism ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*metabolism ; Receptors, Notch/metabolism ; Signal Transduction
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Formation of the first peptide bond: the structure of EF-P bound to the 70S ribosome (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-08-22
    Description: Elongation factor P (EF-P) is an essential protein that stimulates the formation of the first peptide bond in protein synthesis. Here we report the crystal structure of EF-P bound to the Thermus thermophilus 70S ribosome along with the initiator transfer RNA N-formyl-methionyl-tRNA(i) (fMet-tRNA(i)(fMet)) and a short piece of messenger RNA (mRNA) at a resolution of 3.5 angstroms. EF-P binds to a site located between the binding site for the peptidyl tRNA (P site) and the exiting tRNA (E site). It spans both ribosomal subunits with its amino-terminal domain positioned adjacent to the aminoacyl acceptor stem and its carboxyl-terminal domain positioned next to the anticodon stem-loop of the P site-bound initiator tRNA. Domain II of EF-P interacts with the ribosomal protein L1, which results in the largest movement of the L1 stalk that has been observed in the absence of ratcheting of the ribosomal subunits. EF-P facilitates the proper positioning of the fMet-tRNA(i)(fMet) for the formation of the first peptide bond during translation initiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296453/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296453/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blaha, Gregor -- Stanley, Robin E -- Steitz, Thomas A -- GM22778/GM/NIGMS NIH HHS/ -- P01 GM022778/GM/NIGMS NIH HHS/ -- P01 GM022778-36/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Aug 21;325(5943):966-70. doi: 10.1126/science.1175800.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biophysics, Yale University, New Haven, CT 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19696344" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Models, Molecular ; *Peptide Chain Initiation, Translational ; Peptide Elongation Factors/*chemistry/*metabolism ; Protein Conformation ; Protein Structure, Tertiary ; RNA, Bacterial/chemistry/metabolism ; RNA, Messenger/chemistry/metabolism ; RNA, Transfer, Met/chemistry/metabolism ; Ribosomal Proteins/metabolism ; Ribosome Subunits, Large, Bacterial/metabolism ; Ribosome Subunits, Small, Bacterial/metabolism ; Ribosomes/*metabolism ; Thermus thermophilus/chemistry/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 95
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    A dimeric structure for archaeal box C/D small ribonucleoproteins (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-12
    Description: Methylation of ribosomal RNA (rRNA) is required for optimal protein synthesis. Multiple 2'-O-ribose methylations are carried out by box C/D guide ribonucleoproteins [small ribonucleoproteins (sRNPs) and small nucleolar ribonucleoproteins (snoRNPs)], which are conserved from archaea to eukaryotes. Methylation is dictated by base pairing between the specific guide RNA component of the sRNP or snoRNP and the target rRNA. We determined the structure of a reconstituted and catalytically active box C/D sRNP from the archaeon Methanocaldococcus jannaschii by single-particle electron microscopy. We found that archaeal box C/D sRNPs unexpectedly formed a dimeric structure with an alternative organization of their RNA and protein components that challenges the conventional view of their architecture. Mutational analysis demonstrated that this di-sRNP structure was relevant for the enzymatic function of archaeal box C/D sRNPs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975540/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bleichert, Franziska -- Gagnon, Keith T -- Brown, Bernard A 2nd -- Maxwell, E Stuart -- Leschziner, Andres E -- Unger, Vinzenz M -- Baserga, Susan J -- R01 GM052581/GM/NIGMS NIH HHS/ -- R01 GM052581-15/GM/NIGMS NIH HHS/ -- R01GM52581/GM/NIGMS NIH HHS/ -- R01GM69699/GM/NIGMS NIH HHS/ -- RR19895/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2009 Sep 11;325(5946):1384-7. doi: 10.1126/science.1176099.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19745151" target="_blank"〉PubMed〈/a〉
    Keywords: Archaeal Proteins/*chemistry/metabolism/ultrastructure ; Base Sequence ; Chromosomal Proteins, Non-Histone/*chemistry ; Methanococcales/*chemistry ; Microscopy, Electron ; Models, Molecular ; Molecular Weight ; Nucleic Acid Conformation ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; RNA, Archaeal/*chemistry/ultrastructure ; Ribonucleoproteins/*chemistry/metabolism/ultrastructure
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-01-20
    Description: Bacterial multidrug tolerance is largely responsible for the inability of antibiotics to eradicate infections and is caused by a small population of dormant bacteria called persisters. HipA is a critical Escherichia coli persistence factor that is normally neutralized by HipB, a transcription repressor, which also regulates hipBA expression. Here, we report multiple structures of HipA and a HipA-HipB-DNA complex. HipA has a eukaryotic serine/threonine kinase-like fold and can phosphorylate the translation factor EF-Tu, suggesting a persistence mechanism via cell stasis. The HipA-HipB-DNA structure reveals the HipB-operator binding mechanism, approximately 70 degrees DNA bending, and unexpected HipA-DNA contacts. Dimeric HipB interacts with two HipA molecules to inhibit its kinase activity through sequestration and conformational inactivation. Combined, these studies suggest mechanisms for HipA-mediated persistence and its neutralization by HipB.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764309/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764309/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schumacher, Maria A -- Piro, Kevin M -- Xu, Weijun -- Hansen, Sonja -- Lewis, Kim -- Brennan, Richard G -- AI048593/AI/NIAID NIH HHS/ -- GM061162/GM/NIGMS NIH HHS/ -- GM074815/GM/NIGMS NIH HHS/ -- R01 GM061162/GM/NIGMS NIH HHS/ -- R01 GM061162-09/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Jan 16;323(5912):396-401. doi: 10.1126/science.1163806.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Unit 1000, Houston, TX 77030, USA. maschuma@mdanderson.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19150849" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Crystallization ; Crystallography, X-Ray ; DNA, Bacterial/chemistry/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dimerization ; *Drug Tolerance ; Escherichia coli/chemistry/*drug effects/genetics/*metabolism ; Escherichia coli Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism ; Models, Molecular ; Nucleic Acid Conformation ; Operator Regions, Genetic ; Operon ; Peptide Elongation Factor Tu/metabolism ; Phosphorylation ; Protein Conformation ; Protein Folding ; Protein Kinase Inhibitors/metabolism ; Protein Kinases/chemistry/metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-19
    Description: Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of genes responsible for iron uptake, release, use, and storage through the actions of the iron regulatory proteins IRP1 and IRP2. However, the manner in which iron levels are sensed to affect IRP2 activity is poorly understood. We found that an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation. The stability of FBXL5 itself was regulated, accumulating under iron- and oxygen-replete conditions and degraded upon iron depletion. FBXL5 contains an iron- and oxygen-binding hemerythrin domain that acted as a ligand-dependent regulatory switch mediating FBXL5's differential stability. These observations suggest a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582197/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582197/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Salahudeen, Ameen A -- Thompson, Joel W -- Ruiz, Julio C -- Ma, He-Wen -- Kinch, Lisa N -- Li, Qiming -- Grishin, Nick V -- Bruick, Richard K -- C06 RR 15437-01/RR/NCRR NIH HHS/ -- CA115962/CA/NCI NIH HHS/ -- R01 CA115962/CA/NCI NIH HHS/ -- R01 CA115962-05/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Oct 30;326(5953):722-6. doi: 10.1126/science.1176326. Epub 2009 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19762597" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Cell Line ; F-Box Proteins/chemistry/*metabolism ; HeLa Cells ; Hemerythrin/*metabolism ; Homeostasis ; Humans ; Iron/*metabolism ; Iron Regulatory Protein 2/metabolism ; Oxygen/metabolism ; Protein Structure, Tertiary ; RNA, Small Interfering ; Recombinant Fusion Proteins/metabolism ; Ubiquitin-Protein Ligases/chemistry/*metabolism
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 98
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    Control of iron homeostasis by an iron-regulated ubiquitin ligase (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-19
    Description: Eukaryotic cells require iron for survival and have developed regulatory mechanisms for maintaining appropriate intracellular iron concentrations. The degradation of iron regulatory protein 2 (IRP2) in iron-replete cells is a key event in this pathway, but the E3 ubiquitin ligase responsible for its proteolysis has remained elusive. We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. Thus, iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929180/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929180/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vashisht, Ajay A -- Zumbrennen, Kimberly B -- Huang, Xinhua -- Powers, David N -- Durazo, Armando -- Sun, Dahui -- Bhaskaran, Nimesh -- Persson, Anja -- Uhlen, Mathias -- Sangfelt, Olle -- Spruck, Charles -- Leibold, Elizabeth A -- Wohlschlegel, James A -- GM45201/GM/NIGMS NIH HHS/ -- R01 GM045201/GM/NIGMS NIH HHS/ -- R01 GM045201-17/GM/NIGMS NIH HHS/ -- R01 GM089778/GM/NIGMS NIH HHS/ -- R01 GM089778-01A1/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Oct 30;326(5953):718-21. doi: 10.1126/science.1176333. Epub 2009 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19762596" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Cullin Proteins/metabolism ; F-Box Proteins/*metabolism ; Hemerythrin/metabolism ; Homeostasis ; Humans ; Iron/*metabolism ; Iron Regulatory Protein 1/metabolism ; Iron Regulatory Protein 2/*metabolism ; Oxygen/metabolism ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; SKP Cullin F-Box Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/*metabolism
    Print ISSN: 0036-8075
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  • 99
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    Distinct domains of tRNA synthetase recognize the same base pair (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-01-04
    Description: Synthesis of proteins containing errors (mistranslation) is prevented by aminoacyl transfer RNA synthetases through their accurate aminoacylation of cognate tRNAs and their ability to correct occasional errors of aminoacylation by editing reactions. A principal source of mistranslation comes from mistaking glycine or serine for alanine, which can lead to serious cell and animal pathologies, including neurodegeneration. A single specific G.U base pair (G3.U70) marks a tRNA for aminoacylation by alanyl-tRNA synthetase. Mistranslation occurs when glycine or serine is joined to the G3.U70-containing tRNAs, and is prevented by the editing activity that clears the mischarged amino acid. Previously it was assumed that the specificity for recognition of tRNA(Ala) for editing was provided by the same structural determinants as used for aminoacylation. Here we show that the editing site of alanyl-tRNA synthetase, as an artificial recombinant fragment, targets mischarged tRNA(Ala) using a structural motif unrelated to that for aminoacylation so that, remarkably, two motifs (one for aminoacylation and one for editing) in the same enzyme independently can provide determinants for tRNA(Ala) recognition. The structural motif for editing is also found naturally in genome-encoded protein fragments that are widely distributed in evolution. These also recognize mischarged tRNA(Ala). Thus, through evolution, three different complexes with the same tRNA can guard against mistaking glycine or serine for alanine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beebe, Kirk -- Mock, Marissa -- Merriman, Eve -- Schimmel, Paul -- England -- Nature. 2008 Jan 3;451(7174):90-3. doi: 10.1038/nature06454.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18172502" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine-tRNA Ligase/*chemistry/*metabolism ; Amino Acid Motifs ; *Base Pairing ; Binding Sites ; Escherichia coli/enzymology ; Peptide Fragments/chemistry/metabolism ; Protein Biosynthesis ; Protein Structure, Tertiary ; RNA, Transfer, Ala/*chemistry/genetics/*metabolism ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structure of the guide-strand-containing argonaute silencing complex (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-30
    Description: The slicer activity of the RNA-induced silencing complex is associated with argonaute, the RNase H-like PIWI domain of which catalyses guide-strand-mediated sequence-specific cleavage of target messenger RNA. Here we report on the crystal structure of Thermus thermophilus argonaute bound to a 5'-phosphorylated 21-base DNA guide strand, thereby identifying the nucleic-acid-binding channel positioned between the PAZ- and PIWI-containing lobes, as well as the pivot-like conformational changes associated with complex formation. The bound guide strand is anchored at both of its ends, with the solvent-exposed Watson-Crick edges of stacked bases 2 to 6 positioned for nucleation with the mRNA target, whereas two critically positioned arginines lock bases 10 and 11 at the cleavage site into an unanticipated orthogonal alignment. Biochemical studies indicate that key amino acid residues at the active site and those lining the 5'-phosphate-binding pocket made up of the Mid domain are critical for cleavage activity, whereas alterations of residues lining the 2-nucleotide 3'-end-binding pocket made up of the PAZ domain show little effect.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689319/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689319/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yanli -- Sheng, Gang -- Juranek, Stefan -- Tuschl, Thomas -- Patel, Dinshaw J -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI068776/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Nov 13;456(7219):209-13. doi: 10.1038/nature07315. Epub 2008 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18754009" target="_blank"〉PubMed〈/a〉
    Keywords: Aptamers, Nucleotide/metabolism ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; *Gene Silencing ; Hydrogen Bonding ; *Models, Molecular ; Mutation ; Protein Structure, Tertiary ; RNA/metabolism ; Thermus thermophilus/*chemistry/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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