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

Autor: Chen C; Biophysics, University of Michigan, Ann Arbor, MI, 48109, USA.; Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany., Piano V; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.; Institute of Human Genetics, University Hospital Cologne, Cologne, 50931, Germany., Alex A; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany., Han SJY; Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA., Huis In 't Veld PJ; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany., Roy B; Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Fergle D; Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Musacchio A; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.; Centre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, 45141, Germany., Joglekar AP; Biophysics, University of Michigan, Ann Arbor, MI, 48109, USA. ajitj@umich.edu.; Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. ajitj@umich.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Mar 18; Vol. 14 (1), pp. 1529. Date of Electronic Publication: 2023 Mar 18.
DOI: 10.1038/s41467-023-37235-z
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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