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Mechanistic insight into TRIP13-catalyzed Mad2 structural transition and spindle checkpoint silencing.


ABSTRACT: The spindle checkpoint maintains genomic stability and prevents aneuploidy. Unattached kinetochores convert the latent open conformer of the checkpoint protein Mad2 (O-Mad2) to the active closed conformer (C-Mad2), bound to Cdc20. C-Mad2-Cdc20 is incorporated into the mitotic checkpoint complex (MCC), which inhibits the anaphase-promoting complex/cyclosome (APC/C). The C-Mad2-binding protein p31comet and the ATPase TRIP13 promote MCC disassembly and checkpoint silencing. Here, using nuclear magnetic resonance (NMR) spectroscopy, we show that TRIP13 and p31comet catalyze the conversion of C-Mad2 to O-Mad2, without disrupting its stably folded core. We determine the crystal structure of human TRIP13, and identify functional TRIP13 residues that mediate p31comet-Mad2 binding and couple ATP hydrolysis to local unfolding of Mad2. TRIP13 and p31comet prevent APC/C inhibition by MCC components, but cannot reactivate APC/C already bound to MCC. Therefore, TRIP13-p31comet intercepts and disassembles free MCC not bound to APC/C through mediating the local unfolding of the Mad2 C-terminal region.

SUBMITTER: Brulotte ML 

PROVIDER: S-EPMC5717197 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Mechanistic insight into TRIP13-catalyzed Mad2 structural transition and spindle checkpoint silencing.

Brulotte Melissa L ML   Jeong Byung-Cheon BC   Li Faxiang F   Li Bing B   Yu Eric B EB   Wu Qiong Q   Brautigam Chad A CA   Yu Hongtao H   Luo Xuelian X  

Nature communications 20171205 1


The spindle checkpoint maintains genomic stability and prevents aneuploidy. Unattached kinetochores convert the latent open conformer of the checkpoint protein Mad2 (O-Mad2) to the active closed conformer (C-Mad2), bound to Cdc20. C-Mad2-Cdc20 is incorporated into the mitotic checkpoint complex (MCC), which inhibits the anaphase-promoting complex/cyclosome (APC/C). The C-Mad2-binding protein p31<sup>comet</sup> and the ATPase TRIP13 promote MCC disassembly and checkpoint silencing. Here, using n  ...[more]

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