5wc2

Publication Abstract from PubMed

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(comet) and the ATPase TRIP13 promote MCC disassembly and checkpoint silencing. Here, using nuclear magnetic resonance (NMR) spectroscopy, we show that TRIP13 and p31(comet) 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 p31(comet)-Mad2 binding and couple ATP hydrolysis to local unfolding of Mad2. TRIP13 and p31(comet) prevent APC/C inhibition by MCC components, but cannot reactivate APC/C already bound to MCC. Therefore, TRIP13-p31(comet) intercepts and disassembles free MCC not bound to APC/C through mediating the local unfolding of the Mad2 C-terminal region.

Mechanistic insight into TRIP13-catalyzed Mad2 structural transition and spindle checkpoint silencing.,Brulotte ML, Jeong BC, Li F, Li B, Yu EB, Wu Q, Brautigam CA, Yu H, Luo X Nat Commun. 2017 Dec 5;8(1):1956. doi: 10.1038/s41467-017-02012-2. PMID:29208896^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.