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.
Highlights
The anaphase-promoting complex/cyclosome (APC/C) orchestrates cell cycle progression by controlling the temporal degradation of specific cell cycle regulators
Known degrons of cyclin A2 are dispensable for APC/CCdc[20] activity
Our results reveal that the resistance of cyclin A2 to mitotic checkpoint complex (MCC)-imposed inhibition of APC/C activity is conferred by cooperative binding of four factors: the KEN box, D2 box, ABBA motif and its associated Cks (Fig. 7a, b and Table 1)
Summary
The anaphase-promoting complex/cyclosome (APC/C) orchestrates cell cycle progression by controlling the temporal degradation of specific cell cycle regulators. 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. Transgenic mice overexpressing cyclin A2 in mammary glands exhibited hyperplasia and nuclear abnormalities[19] These studies underlie the importance of understanding the mechanisms responsible for targeted cyclin A2 degradation. 21–23), and obstructing the E2 binding site to suppress APC/ C’s catalytic activity[22,23] Both the N-terminal 165 residues of human cyclin A2 and the Cdk-associated cofactor Cks are necessary and sufficient to allow SAC-resistant degradation of cyclin A216,24,25, yet the exact degrons responsible for cyclin A2 degradation are unknown. Our data indicate that the MCC-repressed state of the APC/C (APC/CMCC) is responsible for ubiquitinating cyclin A2 during an active SAC by directly engaging cyclin A2. We reveal two distinct binding modes of cyclin A2 to APC/ CCdc[20] that influence its ubiquitination efficiency
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