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Nat Commun. 2019 Aug 27;10(1):3863. doi: 10.1038/s41467-019-11833-2.

Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C.

Author information

1
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
2
Max Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.
3
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. dbarford@mrc-lmb.cam.ac.uk.

Abstract

The anaphase-promoting complex/cyclosome (APC/C) orchestrates cell cycle progression by controlling the temporal degradation of specific cell cycle regulators. Although cyclin A2 and cyclin B1 are both targeted for degradation by the APC/C, during the spindle assembly checkpoint (SAC), the mitotic checkpoint complex (MCC) represses APC/C's activity towards cyclin B1, but not cyclin A2. Through structural, biochemical and in vivo analysis, we identify a non-canonical D box (D2) that is critical for cyclin A2 ubiquitination in vitro and degradation in vivo. During the SAC, cyclin A2 is ubiquitinated by the repressed APC/C-MCC, mediated by the cooperative engagement of its KEN and D2 boxes, ABBA motif, and the cofactor Cks. Once the SAC is satisfied, cyclin A2 binds APC/C-Cdc20 through two mutually exclusive binding modes, resulting in differential ubiquitination efficiency. Our findings reveal that a single substrate can engage an E3 ligase through multiple binding modes, affecting its degradation timing and efficiency.

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