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TitleCyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C.
Journal, issue, pagesNat Commun, Vol. 10, Issue 1, Page 3863, Year 2019
Publish dateAug 27, 2019
AuthorsSuyang Zhang / Thomas Tischer / David Barford /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:31455778 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.7 Å
Structure data

EMDB-4463:
Cryo-EM reconstruction of the APC/C-MCC-Cdk2-cyclinA2-Cks2 complex in the open conformation
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-4464:
Cryo-EM reconstruction of the APC/C-MCC-Cdk2-cyclinA2-Cks2 complex in the closed conformation
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-4465, PDB-6q6g:
Cryo-EM structure of the APC/C-Cdc20-Cdk2-cyclinA2-Cks2 complex, the D1 box class
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-4466, PDB-6q6h:
Cryo-EM structure of the APC/C-Cdc20-Cdk2-cyclinA2-Cks2 complex, the D2 box class
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-4467:
Cryo-EM structure of the APC/C-Cdc20-Cdk2-cyclinA2delD1-Cks2 complex (with the D1 box mutated)
Method: EM (single particle) / Resolution: 3.7 Å

Source
  • homo sapiens (human)
KeywordsCELL CYCLE / spindle assembly checkpoint / anaphase-promoting complex / cyclin / ubiquitination

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