Mechanistic insight into TRIP13-catalyzed Mad2 structural transition and spindle checkpoint silencing.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29208896.
- Also identified by DOI 10.1038/s41467-017-02012-2 and PMC identifier 5717197.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 p31<sup>comet</sup> and the ATPase TRIP13 promote MCC disassembly and checkpoint silencing. Here, using nuclear magnetic resonance (NMR) spectroscopy, we show that TRIP13 and p31<sup>comet</sup> 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<sup>comet</sup>-Mad2 binding and couple ATP hydrolysis to local unfolding of Mad2. TRIP13 and p31<sup>comet</sup> prevent APC/C inhibition by MCC components, but cannot reactivate APC/C already bound to MCC. Therefore, TRIP13-p31<sup>comet</sup> intercepts and disassembles free MCC not bound to APC/C through mediating the local unfolding of the Mad2 C-terminal region.
Medical subject headings
- ATPases Associated with Diverse Cellular Activities
- Adaptor Proteins, Signal Transducing
- Cdc20 Proteins
- Cell Cycle Proteins
- M Phase Cell Cycle Checkpoints
- Mad2 Proteins
- Nuclear Proteins