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Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C

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  • Suyang Zhang

    (MRC Laboratory of Molecular Biology
    Max Planck Institute for Biophysical Chemistry)

  • Thomas Tischer

    (MRC Laboratory of Molecular Biology)

  • David Barford

    (MRC Laboratory of Molecular Biology)

Abstract

The anaphase-promoting complex/cyclosome (APC/C) orchestrates cell cycle progression by controlling the temporal degradation of specific cell cycle regulators. Although cyclin A2 and cyclin B1 are both targeted for degradation by the APC/C, during the spindle assembly checkpoint (SAC), the mitotic checkpoint complex (MCC) represses APC/C’s activity towards cyclin B1, but not cyclin A2. Through structural, biochemical and in vivo analysis, we identify a non-canonical D box (D2) that is critical for cyclin A2 ubiquitination in vitro and degradation in vivo. During the SAC, cyclin A2 is ubiquitinated by the repressed APC/C-MCC, mediated by the cooperative engagement of its KEN and D2 boxes, ABBA motif, and the cofactor Cks. Once the SAC is satisfied, cyclin A2 binds APC/C-Cdc20 through two mutually exclusive binding modes, resulting in differential ubiquitination efficiency. Our findings reveal that a single substrate can engage an E3 ligase through multiple binding modes, affecting its degradation timing and efficiency.

Suggested Citation

  • Suyang Zhang & Thomas Tischer & David Barford, 2019. "Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11833-2
    DOI: 10.1038/s41467-019-11833-2
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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. Xiaohua Xu & Chou-Wei Chang & Min Li & Kenneth Omabe & Nhung Le & Yi-Hsuan Chen & Feng Liang & Yilun Liu, 2023. "DNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. 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.

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