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

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.
Mesh Terms:
Amino Acid Motifs, Anaphase-Promoting Complex-Cyclosome, CDC2-CDC28 Kinases, Cdc20 Proteins, Cell Cycle Proteins, Cryoelectron Microscopy, Cyclin A2, HEK293 Cells, Humans, Intravital Microscopy, M Phase Cell Cycle Checkpoints, Models, Molecular, Protein Binding, Proteolysis, Spindle Apparatus, Substrate Specificity, Ubiquitination
Nat Commun
Date: Dec. 27, 2018
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