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  • 1
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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
    Published by Nature Publishing Group (NPG)
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  • 2
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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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  • 3
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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
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  • 4
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    Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1 (2013)
    Nature Publishing Group (NPG)
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    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
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  • 5
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    Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-07
    Description: Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal alpha-helix (alphaN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the alphaN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4)(2) tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4)(2). We show that the Rtt106-(H3-H4)(2) interaction is important for gene silencing and the DNA damage response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439842/" 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/PMC3439842/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Dan -- Hu, Qi -- Li, Qing -- Thompson, James R -- Cui, Gaofeng -- Fazly, Ahmed -- Davies, Brian A -- Botuyan, Maria Victoria -- Zhang, Zhiguo -- Mer, Georges -- P50 CA108961/CA/NCI NIH HHS/ -- R01 CA132878/CA/NCI NIH HHS/ -- R01 CA132878-04/CA/NCI NIH HHS/ -- R01 GM072719/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 5;483(7387):104-7. doi: 10.1038/nature10861.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22307274" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Binding Sites ; Crystallography, X-Ray ; DNA Damage ; Gene Silencing ; Genomic Instability ; Histones/*chemistry/*metabolism ; Lysine/analogs & derivatives/chemistry/metabolism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Chaperones/*chemistry/genetics/*metabolism ; Mutation/genetics ; Pliability ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Xenopus laevis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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