title: Atomic structure of the APC/C and its mechanism of protein ubiquitination.
abstract: The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit. Its regulation by coactivator subunits, phosphorylation, the mitotic checkpoint complex and interphase early mitotic inhibitor 1 (Emi1) ensures the correct order and timing of distinct cell-cycle transitions. Here we use cryo-electron microscopy to determine atomic structures of APC/C-coactivator complexes with either Emi1 or a UbcH10-ubiquitin conjugate. These structures define the architecture of all APC/C subunits, the position of the catalytic module and explain how Emi1 mediates inhibition of the two E2s UbcH10 and Ube2S. Definition of Cdh1 interactions with the APC/C indicates how they are antagonized by Cdh1 phosphorylation. The structure of the APC/C with UbcH10-ubiquitin reveals insights into the initiating ubiquitination reaction. Our results provide a quantitative framework for the design of future experiments to investigate APC/C functions in vivo.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Leifu
authors.initials: L
authors.lastname: Chang
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Ziguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: McLaughlin
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Barford
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D015703:Antigens, CD; D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D064197:Apc10 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D064198:Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000737:chemistry / Q000378:metabolism; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000737:chemistry / Q000378:metabolism; D064196:Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D044783:F-Box Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D054875:Ubiquitination
chemical_list: C577335:ANAPC1 protein, human; C577455:ANAPC10 protein, human; C115681:APC2 protein, human; D015703:Antigens, CD; D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome; D064197:Apc10 Subunit, Anaphase-Promoting Complex-Cyclosome; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D064196:Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome; C577440:CDC23 protein, human; C577366:CDC27 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D021122:Protein Subunits; D025801:Ubiquitin; C105156:UBE2C protein, human; C544962:Ube2S protein, human; D044763:Ubiquitin-Conjugating Enzymes; C577351:ANAPC11 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome; D064198:Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome; D008239:Lysine