Molecular basis of APC/C regulation by the spindle assembly checkpoint.
Abstract
In the dividing eukaryotic cell, the spindle assembly checkpoint (SAC) ensures that each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex (APC/C), the E3 ubiquitin ligase responsible for initiating chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), which inhibits the APC/C and delays chromosome segregation. By cryo-electron microscopy, here we determine the near-atomic resolution structure of a human APC/C–MCC complex (APC/C(MCC)). Degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit responsible for substrate interactions. BubR1 also obstructs binding of the initiating E2 enzyme UbcH10 to repress APC/C ubiquitination activity. Conformational variability of the complex enables UbcH10 association, and structural analysis shows how the Cdc20 subunit intrinsic to the MCC (Cdc20(MCC)) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced.
Collections
Subject
Kinetochores
Humans
Ubiquitin-Conjugating Enzymes
Ubiquitin-Protein Ligases
Protein-Serine-Threonine Kinases
Cell Cycle Proteins
Protein Subunits
Cryoelectron Microscopy
Chromosome Segregation
Protein Conformation
Protein Binding
Structure-Activity Relationship
Models, Molecular
Ubiquitination
Biocatalysis
M Phase Cell Cycle Checkpoints
Spindle Apparatus
Anaphase-Promoting Complex-Cyclosome
Cdc20 Proteins
Research team
Molecular mechanisms of cell cycle regulation
Language
eng
Date accepted
2016-07-06
License start date
2016-08-10
Citation
Nature, 2016, 536 (7617), pp. 431 - 436
Publisher
NATURE PUBLISHING GROUP
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