|Title||Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C.|
|Journal, issue, pages||Nat Commun, Vol. 10, Issue 1, Page 3863, Year 2019|
|Publish date||Aug 27, 2019|
|Authors||Suyang Zhang / Thomas Tischer / David Barford /|
|PubMed 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 ...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 links||Nat Commun / PubMed:31455778 / PubMed Central|
|Methods||EM (single particle)|
|Resolution||3.2 - 3.7 Å|
|Keywords||Amino Acid Motifs / Anaphase-Promoting Complex-Cyclosome / CCNA2 protein, human / CDC2-CDC28 Kinases / CDC20 protein, human / CKS2 protein, human / 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 / CELL CYCLE / spindle assembly checkpoint / anaphase-promoting complex / cyclin|
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