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Molecular mechanisms of APC/C release from spindle assembly checkpoint inhibition by APC/C SUMOylation

DOI: 10.1016/j.celrep.2021.108929 DOI Help

Authors: Stanislau Yatskevich (MRC Laboratory of Molecular Biology) , Jessie S. Kroonen (Leiden University Medical Center) , Claudio Alfieri (MRC Laboratory of Molecular Biology) , Thomas Tischer (MRC Laboratory of Molecular Biology) , Anna C. Howes (MRC Laboratory of Molecular Biology) , Linda Clijsters (Leiden University Medical Center) , Jing Yang (MRC Laboratory of Molecular Biology) , Ziguo Zhang (MRC Laboratory of Molecular Biology) , Kaige Yan (MRC Laboratory of Molecular Biology) , Alfred C. O. Vertegaal (Leiden University Medical Center) , David Barford (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 34

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 13708

Open Access Open Access

Abstract: The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls cell cycle transitions. Its regulation by the spindle assembly checkpoint (SAC) is coordinated with the attachment of sister chromatids to the mitotic spindle. APC/C SUMOylation on APC4 ensures timely anaphase onset and chromosome segregation. To understand the structural and functional consequences of APC/C SUMOylation, we reconstituted SUMOylated APC/C for electron cryo-microscopy and biochemical analyses. SUMOylation of the APC/C causes a substantial rearrangement of the WHB domain of APC/C’s cullin subunit (APC2WHB). Although APC/CCdc20 SUMOylation results in a modest impact on normal APC/CCdc20 activity, repositioning APC2WHB reduces the affinity of APC/CCdc20 for the mitotic checkpoint complex (MCC), the effector of the SAC. This attenuates MCC-mediated suppression of APC/CCdc20 activity, allowing for more efficient ubiquitination of APC/CCdc20 substrates in the presence of the MCC. Thus, SUMOylation stimulates the reactivation of APC/CCdc20 when the SAC is silenced, contributing to timely anaphase onset.

Journal Keywords: APC/C; SUMOylation; SAC; MCC; WHB domain; ubiquitination; cell cycle

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond


Discipline Tags:

Life Sciences & Biotech Chemistry Biochemistry

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)