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

Elyse S. Fischer (), Conny W. H. Yu, Johannes F. Hevler, Stephen H. McLaughlin, Sarah L. Maslen, Albert J. R. Heck, Stefan M. V. Freund and David Barford ()
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Elyse S. Fischer: Cambridge Biomedical Campus
Conny W. H. Yu: Cambridge Biomedical Campus
Johannes F. Hevler: University of Utrecht
Stephen H. McLaughlin: Cambridge Biomedical Campus
Sarah L. Maslen: Cambridge Biomedical Campus
Albert J. R. Heck: University of Utrecht
Stefan M. V. Freund: Cambridge Biomedical Campus
David Barford: Cambridge Biomedical Campus

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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 (Mad1CTD). We additionally identify flexibility of Mad1:Mad2 that suggests how the Cdc20:Mad1CTD 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.

Date: 2022
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DOI: 10.1038/s41467-022-34058-2

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