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Molecular architecture and mechanism of the anaphase-promoting complex

Author

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  • Leifu Chang

    (Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
    MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
    Present address: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK (L.C., Z.Z., J.Y. and D.B.).)

  • Ziguo Zhang

    (Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
    MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
    Present address: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK (L.C., Z.Z., J.Y. and D.B.).)

  • Jing Yang

    (Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
    MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
    Present address: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK (L.C., Z.Z., J.Y. and D.B.).)

  • Stephen H. McLaughlin

    (MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK)

  • David Barford

    (Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
    MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
    Present address: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK (L.C., Z.Z., J.Y. and D.B.).)

Abstract

The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of the G1 phase of the cell cycle. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C–substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-electron microscopy reconstruction of a human APC/C–coactivator–substrate complex at 7.4 Å resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that the coactivator promotes a profound allosteric transition involving displacement of the cullin-RING catalytic subunits relative to the degron-recognition module of coactivator and APC10. This transition is accompanied by increased flexibility of the cullin-RING subunits and enhanced affinity for UBCH10–ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity.

Suggested Citation

  • Leifu Chang & Ziguo Zhang & Jing Yang & Stephen H. McLaughlin & David Barford, 2014. "Molecular architecture and mechanism of the anaphase-promoting complex," Nature, Nature, vol. 513(7518), pages 388-393, September.
    • Handle: RePEc:nat:nature:v:513:y:2014:i:7518:d:10.1038_nature13543
    DOI: 10.1038/nature13543
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    Cited by:

    1. Christopher Thomas & Benjamin Wetherall & Mark D. Levasseur & Rebecca J. Harris & Scott T. Kerridge & Jonathan M. G. Higgins & Owen R. Davies & Suzanne Madgwick, 2021. "A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Sang Bae Lee & Luciano Garofano & Aram Ko & Fulvio D’Angelo & Brulinda Frangaj & Danika Sommer & Qiwen Gan & KyeongJin Kim & Timothy Cardozo & Antonio Iavarone & Anna Lasorella, 2022. "Regulated interaction of ID2 with the anaphase-promoting complex links progression through mitosis with reactivation of cell-type-specific transcription," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Nairi Hartooni & Jongmin Sung & Ankur Jain & David O. Morgan, 2022. "Single-molecule analysis of specificity and multivalency in binding of short linear substrate motifs to the APC/C," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. 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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