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Orthorhombic P212121 Structure of Human Mad1 C-terminal Domain in Complex with Phosphorylated Bub1 CD1 Domain
Structural highlights
DiseaseMD1L1_HUMAN Defects in MAD1L1 are involved in the development and/or progression of various types of cancer. FunctionMD1L1_HUMAN Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. May recruit MAD2L1 to unattached kinetochores. Has a role in the correct positioning of the septum. Required for anchoring MAD2L1 to the nuclear periphery. Binds to the TERT promoter and represses telomerase expression, possibly by interfering with MYC binding.[1] [2] [3] Publication Abstract from PubMedDuring metaphase, in response to improper kinetochore-microtubule attachments, the spindle assembly checkpoint (SAC) activates the mitotic checkpoint complex (MCC), an inhibitor of the anaphase-promoting complex/cyclosome (APC/C). This process is orchestrated by the kinase Mps1, which initiates the assembly of the MCC onto kinetochores through a sequential phosphorylation-dependent signalling cascade. The Mad1-Mad2 complex, which is required to catalyse MCC formation, is targeted to kinetochores through a direct interaction with the phosphorylated conserved domain 1 (CD1) of Bub1. Here, we present the crystal structure of the C-terminal domain of Mad1 (Mad1(CTD) ) bound to two phosphorylated Bub1(CD1) peptides at 1.75 A resolution. This interaction is mediated by phosphorylated Bub1 Thr461, which not only directly interacts with Arg617 of the Mad1 RLK (Arg-Leu-Lys) motif, but also directly acts as an N-terminal cap to the CD1 alpha-helix dipole. Surprisingly, only one Bub1(CD1) peptide binds to the Mad1 homodimer in solution. We suggest that this stoichiometry is due to inherent asymmetry in the coiled-coil of Mad1(CTD) and has implications for how the Mad1-Bub1 complex at kinetochores promotes efficient MCC assembly. Molecular mechanism of Mad1 kinetochore targeting by phosphorylated Bub1.,Fischer ES, Yu CWH, Bellini D, McLaughlin SH, Orr CM, Wagner A, Freund SMV, Barford D EMBO Rep. 2021 Jul 5;22(7):e52242. doi: 10.15252/embr.202052242. Epub 2021 May , 19. PMID:34013668[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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