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Nature. 2014 Sep 18;513(7518):388-393. doi: 10.1038/nature13543. Epub 2014 Jul 20.

Molecular architecture and mechanism of the anaphase-promoting complex.

Author information

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.
#
Contributed equally

Abstract

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 Å 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.

PMID:
25043029
PMCID:
PMC4456660
DOI:
10.1038/nature13543
[Indexed for MEDLINE]
Free PMC Article

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