The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex

Chu Chen, Valentina Piano, Amal Alex, Simon J. Y. Han, Pim J. Huis in ’t Veld, Babhrubahan Roy, Daniel Fergle, Andrea Musacchio and Ajit P. Joglekar ()
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Chu Chen: University of Michigan
Valentina Piano: Max Planck Institute of Molecular Physiology
Amal Alex: Max Planck Institute of Molecular Physiology
Simon J. Y. Han: University of Michigan Medical School
Pim J. Huis in ’t Veld: Max Planck Institute of Molecular Physiology
Babhrubahan Roy: University of Michigan Medical School
Daniel Fergle: University of Michigan Medical School
Andrea Musacchio: Max Planck Institute of Molecular Physiology
Ajit P. Joglekar: University of Michigan

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract The spindle assembly checkpoint (SAC) safeguards the genome during cell division by generating an effector molecule known as the Mitotic Checkpoint Complex (MCC). The MCC comprises two subcomplexes: BUBR1:BUB3 and CDC20:MAD2, and the formation of CDC20:MAD2 is the rate-limiting step during MCC assembly. Recent studies show that the rate of CDC20:MAD2 formation is significantly accelerated by the cooperative binding of CDC20 to the SAC proteins MAD1 and BUB1. However, the molecular basis for this acceleration is not fully understood. Here, we demonstrate that the structural flexibility of MAD1 at a conserved hinge near the C-terminus is essential for catalytic MCC assembly. This MAD1 hinge enables the MAD1:MAD2 complex to assume a folded conformation in vivo. Importantly, truncating the hinge reduces the rate of MCC assembly in vitro and SAC signaling in vivo. Conversely, mutations that preserve hinge flexibility retain SAC signaling, indicating that the structural flexibility of the hinge, rather than a specific amino acid sequence, is important for SAC signaling. We summarize these observations as the ‘knitting model’ that explains how the folded conformation of MAD1:MAD2 promotes CDC20:MAD2 assembly.

Date: 2023
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DOI: 10.1038/s41467-023-37235-z

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