The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 03 2023
18 03 2023
Historique:
received:
26
06
2022
accepted:
08
03
2023
entrez:
19
3
2023
pubmed:
20
3
2023
medline:
22
3
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36934097
doi: 10.1038/s41467-023-37235-z
pii: 10.1038/s41467-023-37235-z
pmc: PMC10024682
doi:
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
Cell Cycle Proteins
0
Mad2 Proteins
0
Cdc20 Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1529Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R35-GM-126983
Informations de copyright
© 2023. The Author(s).
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