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Structural basis of human separase regulation by securin and CDK1–cyclin B1

Author

Listed:
  • Jun Yu

    (University of Geneva)

  • Pierre Raia

    (University of Geneva)

  • Chloe M. Ghent

    (University of California, San Francisco)

  • Tobias Raisch

    (Max Planck Institute of Molecular Physiology)

  • Yashar Sadian

    (University of Geneva)

  • Simone Cavadini

    (Friedrich Miescher Institute for Biomedical Research)

  • Pramod M. Sabale

    (University of Geneva)

  • David Barford

    (MRC Laboratory of Molecular Biology)

  • Stefan Raunser

    (Max Planck Institute of Molecular Physiology)

  • David O. Morgan

    (University of California, San Francisco)

  • Andreas Boland

    (University of Geneva)

Abstract

In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex1. Separation of chromosomes during anaphase is triggered by separase—a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD212–4). Separase is activated by degradation of its inhibitors, securin5 and cyclin B6, but the molecular mechanisms of separase regulation are not clear. Here we used cryogenic electron microscopy to determine the structures of human separase in complex with either securin or CDK1–cyclin B1–CKS1. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. As in Caenorhabditis elegans7 and yeast8, human securin contains its own pseudosubstrate motifs. By contrast, CDK1–cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1–cyclin B1 to block the catalytic sites of both separase and CDK19,10. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine6 that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1–cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation.

Suggested Citation

  • Jun Yu & Pierre Raia & Chloe M. Ghent & Tobias Raisch & Yashar Sadian & Simone Cavadini & Pramod M. Sabale & David Barford & Stefan Raunser & David O. Morgan & Andreas Boland, 2021. "Structural basis of human separase regulation by securin and CDK1–cyclin B1," Nature, Nature, vol. 596(7870), pages 138-142, August.
  • Handle: RePEc:nat:nature:v:596:y:2021:i:7870:d:10.1038_s41586-021-03764-0
    DOI: 10.1038/s41586-021-03764-0
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    Citations

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    Cited by:

    1. Devashish Dwivedi & Daniela Harry & Patrick Meraldi, 2023. "Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Chu Chen & Valentina Piano & Amal Alex & Simon J. Y. Han & Pim J. Huis in ’t Veld & Babhrubahan Roy & Daniel Fergle & Andrea Musacchio & Ajit P. Joglekar, 2023. "The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Jack P. K. Bravo & Cristian Aparicio-Maldonado & Franklin L. Nobrega & Stan J. J. Brouns & David W. Taylor, 2022. "Structural basis for broad anti-phage immunity by DISARM," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Jiaxuan Cheng & Ningning Li & Yunjing Huo & Shangyu Dang & Bik-Kwoon Tye & Ning Gao & Yuanliang Zhai, 2022. "Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Ning Cui & Jun-Tao Zhang & Zhuolin Li & Xiao-Yu Liu & Chongyuan Wang & Hongda Huang & Ning Jia, 2022. "Structural basis for the non-self RNA-activated protease activity of the type III-E CRISPR nuclease-protease Craspase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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