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  • 1
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    A mechanically stabilized receptor-ligand flex-bond important in the vasculature (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-08-21
    Description: Haemostasis in the arteriolar circulation mediated by von Willebrand factor (VWF) binding to platelets is an example of an adhesive interaction that must withstand strong hydrodynamic forces acting on cells. VWF is a concatenated, multifunctional protein that has binding sites for platelets as well as subendothelial collagen. Binding of the A1 domain in VWF to the glycoprotein Ib alpha subunit (GPIbalpha) on the surface of platelets mediates crosslinking of platelets to one another and the formation of a platelet plug for arterioles. The importance of VWF is illustrated by its mutation in von Willebrand disease, a bleeding diathesis. Here, we describe a novel mechanochemical specialization of the A1-GPIbalpha bond for force-resistance. We have developed a method that enables, for the first time, repeated measurements of the binding and unbinding of a receptor and ligand in a single molecule (ReaLiSM). We demonstrate two states of the receptor-ligand bond, that is, a flex-bond. One state is seen at low force; a second state begins to engage at 10 pN with a approximately 20-fold longer lifetime and greater force resistance. The lifetimes of the two states, how force exponentiates lifetime, and the kinetics of switching between the two states are all measured. For the first time, single-molecule measurements on this system are in agreement with bulk phase measurements. The results have important implications not only for how platelets bound to VWF are able to resist force to plug arterioles, but also how increased flow activates platelet plug formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117310/" 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/PMC4117310/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jongseong -- Zhang, Cheng-Zhong -- Zhang, Xiaohui -- Springer, Timothy A -- HL-48675/HL/NHLBI NIH HHS/ -- P01 HL048675/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Aug 19;466(7309):992-5. doi: 10.1038/nature09295.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immune Disease Institute, Children's Hospital Boston and Department of Pathology, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725043" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arterioles/cytology/*physiology ; Blood Coagulation/*physiology ; Blood Platelets/chemistry/cytology/*metabolism ; Cell Line ; Hemorheology ; Humans ; Kinetics ; Ligands ; Membrane Glycoproteins/chemistry/*metabolism ; Mice ; Models, Chemical ; Models, Molecular ; Platelet Glycoprotein GPIb-IX Complex ; Protein Binding ; Protein Structure, Tertiary ; Tensile Strength ; von Willebrand Factor/chemistry/*metabolism
    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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    Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18 (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-15
    Description: Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Benyue -- Chassaing, Benoit -- Shi, Zhenda -- Uchiyama, Robin -- Zhang, Zhan -- Denning, Timothy L -- Crawford, Sue E -- Pruijssers, Andrea J -- Iskarpatyoti, Jason A -- Estes, Mary K -- Dermody, Terence S -- Ouyang, Wenjun -- Williams, Ifor R -- Vijay-Kumar, Matam -- Gewirtz, Andrew T -- AI038296/AI/NIAID NIH HHS/ -- AI080656/AI/NIAID NIH HHS/ -- AI107943/AI/NIAID NIH HHS/ -- DK061417/DK/NIDDK NIH HHS/ -- DK064730/DK/NIDDK NIH HHS/ -- DK56338/DK/NIDDK NIH HHS/ -- R01 AI038296/AI/NIAID NIH HHS/ -- R37 AI038296/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 14;346(6211):861-5. doi: 10.1126/science.1256999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. ; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. ; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. Departments of Pediatrics, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Department of Immunology, Genentech, South San Francisco, CA, USA. ; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ; Department of Nutritional Sciences and Medicine, Pennsylvania State University, University Park, PA 16802, USA. ; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. agewirtz@gsu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25395539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diarrhea/immunology/therapy/virology ; Disease Models, Animal ; Feces/virology ; Flagellin/*administration & dosage/immunology ; Homeodomain Proteins/genetics ; *Immunity, Innate ; Interleukin-18/administration & dosage/genetics/*immunology ; Interleukins/administration & dosage/genetics/*immunology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mutation ; Rotavirus Infections/immunology/*prevention & control/therapy ; Toll-Like Receptor 5/genetics/*physiology ; Virus Shedding
    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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  • 3
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    Structural basis for the subunit assembly of the anaphase-promoting complex (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-11
    Description: The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schreiber, Anne -- Stengel, Florian -- Zhang, Ziguo -- Enchev, Radoslav I -- Kong, Eric H -- Morris, Edward P -- Robinson, Carol V -- da Fonseca, Paula C A -- Barford, David -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Feb 10;470(7333):227-32. doi: 10.1038/nature09756.〈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/21307936" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Anaphase-Promoting Complex-Cyclosome ; Animals ; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome ; Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome ; Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome ; Biocatalysis ; Cell Line ; Holoenzymes/chemistry/metabolism/ultrastructure ; Mass Spectrometry ; Microscopy, Electron ; Models, Molecular ; Molecular Weight ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/isolation & purification/metabolism ; Recombinant Proteins/chemistry/metabolism/ultrastructure ; Saccharomyces cerevisiae/chemistry/genetics ; Saccharomyces cerevisiae Proteins/chemistry/isolation & ; purification/metabolism/ultrastructure ; Scattering, Radiation ; Schizosaccharomyces/chemistry ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin-Protein Ligase Complexes/*chemistry/*metabolism/ultrastructure ; Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-08-27
    Description: Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Mitri, Diletta -- Toso, Alberto -- Chen, Jing Jing -- Sarti, Manuela -- Pinton, Sandra -- Jost, Tanja Rezzonico -- D'Antuono, Rocco -- Montani, Erica -- Garcia-Escudero, Ramon -- Guccini, Ilaria -- Da Silva-Alvarez, Sabela -- Collado, Manuel -- Eisenberger, Mario -- Zhang, Zhe -- Catapano, Carlo -- Grassi, Fabio -- Alimonti, Andrea -- England -- Nature. 2014 Nov 6;515(7525):134-7. doi: 10.1038/nature13638. Epub 2014 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2]. ; 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne CH1011, Switzerland. ; Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland. ; Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland. ; 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain. ; Laboratory of Stem Cells in Cancer and Aging, (stemCHUS) Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital (CHUS), E15706 Santiago de Compostela, Spain. ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA. ; Divisions of BioStatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA. ; 1] Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland [2] Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan I-20100, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25156255" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Aging/drug effects ; *Cell Movement ; Disease Progression ; Drug Resistance, Neoplasm ; Humans ; Immunity, Innate ; Interleukin 1 Receptor Antagonist Protein/deficiency/metabolism/secretion ; Interleukin-1alpha/immunology/metabolism ; Male ; Mice ; Myeloid Cells/*cytology/*metabolism/transplantation ; PTEN Phosphohydrolase/deficiency/genetics/metabolism ; Prostatic Neoplasms/drug therapy/immunology/metabolism/*pathology ; Receptors, Chemokine/*metabolism ; Receptors, Interleukin-8B/antagonists & inhibitors ; Taxoids/pharmacology ; Tumor Escape ; Tumor Microenvironment
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-12-18
    Description: Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through alphaB-crystallin (CRYAB), which is known to suppress neuroinflammation. We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wild-type mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shao, Wei -- Zhang, Shu-zhen -- Tang, Mi -- Zhang, Xin-hua -- Zhou, Zheng -- Yin, Yan-qing -- Zhou, Qin-bo -- Huang, Yuan-yuan -- Liu, Ying-jun -- Wawrousek, Eric -- Chen, Teng -- Li, Sheng-bin -- Xu, Ming -- Zhou, Jiang-ning -- Hu, Gang -- Zhou, Jia-wei -- England -- Nature. 2013 Feb 7;494(7435):90-4. doi: 10.1038/nature11748. Epub 2012 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23242137" target="_blank"〉PubMed〈/a〉
    Keywords: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology ; Animals ; Astrocytes/drug effects/*immunology/*metabolism ; Dopaminergic Neurons/drug effects ; Immunity, Innate/drug effects ; Inflammation/chemically induced/genetics/*immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/cytology/immunology ; Neuroprotective Agents/metabolism ; Quinpirole/pharmacology ; Receptors, Dopamine D2/agonists/deficiency/genetics/*metabolism ; Substantia Nigra/cytology/drug effects ; alpha-Crystallin B Chain/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    An armoured Cambrian lobopodian from China with arthropod-like appendages (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-26
    Description: Cambrian fossil Lagerstatten preserving soft-bodied organisms have contributed much towards our understanding of metazoan origins. Lobopodians are a particularly interesting group that diversified and flourished in the Cambrian seas. Resembling 'worms with legs', they have long attracted much attention in that they may have given rise to both Onychophora (velvet worms) and Tardigrada (water bears), as well as to arthropods in general. Here we describe Diania cactiformis gen. et sp. nov. as an 'armoured' lobopodian from the Chengjiang fossil Lagerstatte (Cambrian Stage 3), Yunnan, southwestern China. Although sharing features with other typical lobopodians, it is remarkable for possessing robust and probably sclerotized appendages, with what appear to be articulated elements. In terms of limb morphology it is therefore closer to the arthropod condition, to our knowledge, than any lobopodian recorded until now. Phylogenetic analysis recovers it in a derived position, close to Arthropoda; thus, it seems to belong to a grade of organization close to the point of becoming a true arthropod. Further, D. cactiformis could imply that arthropodization (sclerotization of the limbs) preceded arthrodization (sclerotization of the body). Comparing our fossils with other lobopodian appendage morphologies--see Kerygmachela, Jianshanopodia and Megadictyon--reinforces the hypothesis that the group as a whole is paraphyletic, with different taxa expressing different grades of arthropodization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Jianni -- Steiner, Michael -- Dunlop, Jason A -- Keupp, Helmut -- Shu, Degan -- Ou, Qiang -- Han, Jian -- Zhang, Zhifei -- Zhang, Xingliang -- England -- Nature. 2011 Feb 24;470(7335):526-30. doi: 10.1038/nature09704.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Early Life Institute, State Key Laboratory of Continental Dynamics, Department of Geology, Northwest University, Xi'an 710069, China. liujianni@126.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350485" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arthropods/*anatomy & histology/*classification ; China ; Extinction, Biological ; Extremities/*anatomy & histology ; *Fossils ; *Phylogeny
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-11-26
    Description: The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through recognition of destruction motifs, predominantly the destruction (D)-box and KEN (Lys-Glu-Asn)-box. Although this process is known to involve a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits, the structural basis for substrate recognition and ubiquitylation is not understood. Here we investigate budding yeast APC/C using single-particle electron microscopy and determine a cryo-electron microscopy map of APC/C in complex with the Cdh1 co-activator protein (APC/C(Cdh1)) bound to a D-box peptide at approximately 10 A resolution. We find that a combined catalytic and substrate-recognition module is located within the central cavity of the APC/C assembled from Cdh1, Apc10--a core APC/C subunit previously implicated in substrate recognition--and the cullin domain of Apc2. Cdh1 and Apc10, identified from difference maps, create a co-receptor for the D-box following repositioning of Cdh1 towards Apc10. Using NMR spectroscopy we demonstrate specific D-box-Apc10 interactions, consistent with a role for Apc10 in directly contributing towards D-box recognition by the APC/C(Cdh1) complex. Our results rationalize the contribution of both co-activator and core APC/C subunits to D-box recognition and provide a structural framework for understanding mechanisms of substrate recognition and catalysis by the APC/C.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037847/" 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/PMC3037847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉da Fonseca, Paula C A -- Kong, Eric H -- Zhang, Ziguo -- Schreiber, Anne -- Williams, Mark A -- Morris, Edward P -- Barford, David -- A7403/Cancer Research UK/United Kingdom -- A8022/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Feb 10;470(7333):274-8. doi: 10.1038/nature09625. Epub 2010 Nov 24.〈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/21107322" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Anaphase-Promoting Complex-Cyclosome ; Apc10 Subunit, Anaphase-Promoting Complex-Cyclosome ; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome ; Biocatalysis ; Cdh1 Proteins ; Cell Cycle Proteins/chemistry/*metabolism/ultrastructure ; Cryoelectron Microscopy ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Peptides/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/ultrastructure ; Substrate Specificity ; Ubiquitin-Protein Ligase Complexes/*chemistry/*metabolism/ultrastructure ; Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Serial translocation by means of circular intermediates underlies colour sidedness in cattle (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-03
    Description: Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or 'witrik' (which means white back), as colour-sided animals typically display a white band along their spine. Colour sidedness is documented at least since the Middle Ages and is presently segregating in several cattle breeds around the globe, including in Belgian blue and brown Swiss. Here we report that colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Durkin, Keith -- Coppieters, Wouter -- Drogemuller, Cord -- Ahariz, Naima -- Cambisano, Nadine -- Druet, Tom -- Fasquelle, Corinne -- Haile, Aynalem -- Horin, Petr -- Huang, Lusheng -- Kamatani, Yohichiro -- Karim, Latifa -- Lathrop, Mark -- Moser, Simon -- Oldenbroek, Kor -- Rieder, Stefan -- Sartelet, Arnaud -- Solkner, Johann -- Stalhammar, Hans -- Zelenika, Diana -- Zhang, Zhiyan -- Leeb, Tosso -- Georges, Michel -- Charlier, Carole -- England -- Nature. 2012 Feb 1;482(7383):81-4. doi: 10.1038/nature10757.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liege, 4000-Liege (Sart Tilman), Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22297974" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cattle/classification/*genetics ; Chromosome Mapping ; Chromosomes, Mammalian/*genetics ; DNA Copy Number Variations/genetics ; Gene Duplication/genetics ; Gene Fusion/genetics ; Genome-Wide Association Study ; Genotype ; Hair Color/*genetics ; In Situ Hybridization, Fluorescence ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Translocation, Genetic/*genetics
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  • 9
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    Structure of the mitotic checkpoint complex (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-23
    Description: In mitosis, the spindle assembly checkpoint (SAC) ensures genome stability by delaying chromosome segregation until all sister chromatids have achieved bipolar attachment to the mitotic spindle. The SAC is imposed by the mitotic checkpoint complex (MCC), whose assembly is catalysed by unattached chromosomes and which binds and inhibits the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome segregation. Here, using the crystal structure of Schizosaccharomyces pombe MCC (a complex of mitotic spindle assembly checkpoint proteins Mad2, Mad3 and APC/C co-activator protein Cdc20), we reveal the molecular basis of MCC-mediated APC/C inhibition and the regulation of MCC assembly. The MCC inhibits the APC/C by obstructing degron recognition sites on Cdc20 (the substrate recruitment subunit of the APC/C) and displacing Cdc20 to disrupt formation of a bipartite D-box receptor with the APC/C subunit Apc10. Mad2, in the closed conformation (C-Mad2), stabilizes the complex by optimally positioning the Mad3 KEN-box degron to bind Cdc20. Mad3 and p31(comet) (also known as MAD2L1-binding protein) compete for the same C-Mad2 interface, which explains how p31(comet) disrupts MCC assembly to antagonize the SAC. This study shows how APC/C inhibition is coupled to degron recognition by co-activators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chao, William C H -- Kulkarni, Kiran -- Zhang, Ziguo -- Kong, Eric H -- Barford, David -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Mar 21;484(7393):208-13. doi: 10.1038/nature10896.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division 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/22437499" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Anaphase-Promoting Complex-Cyclosome ; Cdc20 Proteins ; Cdh1 Proteins ; Cell Cycle Proteins/*chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Humans ; *M Phase Cell Cycle Checkpoints ; Mad2 Proteins ; Models, Molecular ; Multiprotein Complexes/*chemistry/metabolism ; Nuclear Proteins/*chemistry/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism ; Schizosaccharomyces/*chemistry ; Schizosaccharomyces pombe Proteins/*chemistry/metabolism ; Spindle Apparatus ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin-Protein Ligase Complexes/antagonists & ; inhibitors/chemistry/metabolism/ultrastructure
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1 (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-12-03
    Description: CAAX proteins have essential roles in multiple signalling pathways, controlling processes such as proliferation, differentiation and carcinogenesis. The approximately 120 mammalian CAAX proteins function at cellular membranes and include the Ras superfamily of small GTPases, nuclear lamins, the gamma-subunit of heterotrimeric GTPases, and several protein kinases and phosphatases. The proper localization of CAAX proteins to cell membranes is orchestrated by a series of post-translational modifications of the carboxy-terminal CAAX motifs (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). These reactions involve prenylation of the cysteine residue, cleavage at the AAX tripeptide and methylation of the carboxyl-prenylated cysteine residue. The major CAAX protease activity is mediated by Rce1 (Ras and a-factor converting enzyme 1), an intramembrane protease (IMP) of the endoplasmic reticulum. Information on the architecture and proteolytic mechanism of Rce1 has been lacking. Here we report the crystal structure of a Methanococcus maripaludis homologue of Rce1, whose endopeptidase specificity for farnesylated peptides mimics that of eukaryotic Rce1. Its structure, comprising eight transmembrane alpha-helices, and catalytic site are distinct from those of other IMPs. The catalytic residues are located approximately 10 A into the membrane and are exposed to the cytoplasm and membrane through a conical cavity that accommodates the prenylated CAAX substrate. We propose that the farnesyl lipid binds to a site at the opening of two transmembrane alpha-helices, which results in the scissile bond being positioned adjacent to a glutamate-activated nucleophilic water molecule. This study suggests that Rce1 is the founding member of a novel IMP family, the glutamate IMPs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864837/" 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/PMC3864837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manolaridis, Ioannis -- Kulkarni, Kiran -- Dodd, Roger B -- Ogasawara, Satoshi -- Zhang, Ziguo -- Bineva, Ganka -- O'Reilly, Nicola -- Hanrahan, Sarah J -- Thompson, Andrew J -- Cronin, Nora -- Iwata, So -- Barford, David -- 100140/Wellcome Trust/United Kingdom -- A2560/Cancer Research UK/United Kingdom -- A7403/Cancer Research UK/United Kingdom -- A8022/Cancer Research UK/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):301-5. doi: 10.1038/nature12754. Epub 2013 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] [3] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. ; Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] Department of Life Sciences, Imperial College, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24291792" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Archaeal Proteins/chemistry/metabolism ; *Biocatalysis ; Conserved Sequence ; Crystallography, X-Ray ; Cysteine/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Endopeptidases/chemistry/metabolism ; Endoplasmic Reticulum/enzymology ; Escherichia coli Proteins/chemistry/metabolism ; Glutamic Acid/metabolism ; Humans ; Membrane Proteins/*chemistry/metabolism ; Metalloendopeptidases/chemistry/metabolism ; Methanococcus/*enzymology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Peptide Hydrolases/*chemistry/classification/*metabolism ; *Prenylation ; Protein Structure, Tertiary ; Proto-Oncogene Proteins p21(ras)/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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