Publication Date:
2014-07-22
Description:
The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of the G1 phase of the cell cycle. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C-substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-electron microscopy reconstruction of a human APC/C-coactivator-substrate complex at 7.4 A resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that the coactivator promotes a profound allosteric transition involving displacement of the cullin-RING catalytic subunits relative to the degron-recognition module of coactivator and APC10. This transition is accompanied by increased flexibility of the cullin-RING subunits and enhanced affinity for UBCH10-ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456660/" 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/PMC4456660/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Leifu -- Zhang, Ziguo -- Yang, Jing -- McLaughlin, Stephen H -- Barford, David -- MC_UP_1201/6/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2014 Sep 18;513(7518):388-93. doi: 10.1038/nature13543. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Structural Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK [3] MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK (L.C., Z.Z., J.Y. and D.B.). [4]. ; 1] Division of Structural Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK [3] MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK (L.C., Z.Z., J.Y. and D.B.). ; 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/25043029" target="_blank"〉PubMed〈/a〉
Keywords:
Allosteric Regulation
;
Anaphase-Promoting Complex-Cyclosome/chemistry/*metabolism/*ultrastructure
;
Apc10 Subunit, Anaphase-Promoting Complex-Cyclosome/chemistry/metabolism
;
Catalytic Domain
;
Cdh1 Proteins/chemistry/metabolism/ultrastructure
;
Cryoelectron Microscopy
;
Humans
;
Models, Molecular
;
Pliability
;
Protein Folding
;
Protein Structure, Secondary
;
Protein Subunits/chemistry/metabolism
;
Ubiquitin/metabolism
;
Ubiquitin-Conjugating Enzymes/metabolism
;
Ubiquitination
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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