BubR1 also obstructs binding of UbcH10 (APC/C’s initiating E2) to repress APC/C ubiquitination activity. They also revealed how degron-like sequences of a MCC subunit (BubR1) block degron recognition sites on Cdc20, the APC/C coactivator subunit (Cdc20 APC/C) responsible for substrate interactions. Using cryo-electron microscopy, Claudio Alfieri and Leifu Chang, in David’s group, have determined the near-atomic resolution structure of an APC/C MCC complex. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), a multimeric assembly that inhibits the APC/C, delaying chromosome segregation. The SAC coordinates the correct attachment of kinetochores to the mitotic spindle with activation of the anaphase-promoting complex/cyclosome (APC/C), a multi-protein complex responsible for initiating chromosome separation. In the dividing eukaryotic cell the spindle assembly checkpoint (SAC) ensures each daughter cell inherits an identical set of chromosomes. Chromosomes attach to the spindle through their kinetochores. The separation of sister chromosomes in mitosis is driven by the mitotic spindle. For the first time, David Barford’s group in the LMB’s Structural Studies Division, have determined the molecular mechanism by which the checkpoint signal in mitosis inhibits a large protein complex (the APC/C) that regulates chromosome separation. Checkpoints either delay cell division, or if unrecoverable, cause cell death. To prevent errors in mitosis cells employ checkpoints that monitor and coordinate the correct order of events.
During eukaryotic cell division (mitosis) the cell’s chromosomes are duplicated and then equally separated into two new daughter cells.
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