4.8 Article

Juxtaposition of Bub1 and Cdc20 on phosphorylated Mad1 during catalytic mitotic checkpoint complex assembly

Journal

NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34058-2

Keywords

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Funding

  1. Gates Cambridge Scholarship
  2. MRC grant [MC_UP_1201/6]
  3. CRUK grant [C576/A14109]
  4. Horizon 2020 INFRAIA project Epic-XS [823839]
  5. Francis Crick Institute through access to the MRC Biomedical NMR Centre
  6. Cancer Research UK [FC001029]
  7. UK Medical Research Council [FC001029]
  8. Wellcome Trust [FC001029]

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This study reveals the complex interaction network required for the formation of the MCC during mitosis. The assembly of MCC is initiated by Mad1 on unattached kinetochores and facilitated by a phosphorylation-dependent scaffold for the binding of Cdc20 and Mad2. This research is of great importance for a better understanding of the regulatory mechanisms of cell division.
Formation of the mitotic checkpoint complex (MCC) is catalysed by a phosphorylation-dependent scaffold. This work provides structural details of how a tripartite Mad1:Bub1:Cdc20 complex presents Cdc20 to Mad2, triggering open-to-closed conversion of Mad2 to assemble the MCC. In response to improper kinetochore-microtubule attachments in mitosis, the spindle assembly checkpoint (SAC) assembles the mitotic checkpoint complex (MCC) to inhibit the anaphase-promoting complex/cyclosome, thereby delaying entry into anaphase. The MCC comprises Mad2:Cdc20:BubR1:Bub3. Its assembly is catalysed by unattached kinetochores on a Mad1:Mad2 platform. Mad1-bound closed-Mad2 (C-Mad2) recruits open-Mad2 (O-Mad2) through self-dimerization. This interaction, combined with Mps1 kinase-mediated phosphorylation of Bub1 and Mad1, accelerates MCC assembly, in a process that requires O-Mad2 to C-Mad2 conversion and concomitant binding of Cdc20. How Mad1 phosphorylation catalyses MCC assembly is poorly understood. Here, we characterized Mps1 phosphorylation of Mad1 and obtained structural insights into a phosphorylation-specific Mad1:Cdc20 interaction. This interaction, together with the Mps1-phosphorylation dependent association of Bub1 and Mad1, generates a tripartite assembly of Bub1 and Cdc20 onto the C-terminal domain of Mad1 (Mad1(CTD)). We additionally identify flexibility of Mad1:Mad2 that suggests how the Cdc20:Mad1(CTD) interaction brings the Mad2-interacting motif (MIM) of Cdc20 near O-Mad2. Thus, Mps1-dependent formation of the MCC-assembly scaffold functions to position and orient Cdc20 MIM near O-Mad2, thereby catalysing formation of C-Mad2:Cdc20.

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