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Molecular basis of APC/C regulation by the spindle assembly checkpoint

Author

Listed:
  • Claudio Alfieri

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Leifu Chang

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Ziguo Zhang

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Jing Yang

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Sarah Maslen

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Mark Skehel

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • David Barford

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

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/CMCC). 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 (Cdc20MCC) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced.

Suggested Citation

  • Claudio Alfieri & Leifu Chang & Ziguo Zhang & Jing Yang & Sarah Maslen & Mark Skehel & David Barford, 2016. "Molecular basis of APC/C regulation by the spindle assembly checkpoint," Nature, Nature, vol. 536(7617), pages 431-436, August.
    • Handle: RePEc:nat:nature:v:536:y:2016:i:7617:d:10.1038_nature19083
    DOI: 10.1038/nature19083
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    Cited by:

    1. Fridolin Gross & Paolo Bonaiuti & Silke Hauf & Andrea Ciliberto, 2018. "Implications of alternative routes to APC/C inhibition by the mitotic checkpoint complex," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-19, September.

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