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Elife. 2015 Apr 28;4. doi: 10.7554/eLife.07367.

TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching.

Author information

1
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, United States.
2
National Resource for Automated Molecular Microscopy, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States.

Abstract

The AAA+ family ATPase TRIP13 is a key regulator of meiotic recombination and the spindle assembly checkpoint, acting on signaling proteins of the conserved HORMA domain family. Here we present the structure of the Caenorhabditis elegans TRIP13 ortholog PCH-2, revealing a new family of AAA+ ATPase protein remodelers. PCH-2 possesses a substrate-recognition domain related to those of the protein remodelers NSF and p97, while its overall hexameric architecture and likely structural mechanism bear close similarities to the bacterial protein unfoldase ClpX. We find that TRIP13, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from a signaling-active 'closed' conformer to an inactive 'open' conformer. We propose that TRIP13 and p31(comet) collaborate to inactivate the spindle assembly checkpoint through MAD2 conformational conversion and disassembly of mitotic checkpoint complexes. A parallel HORMA protein disassembly activity likely underlies TRIP13's critical regulatory functions in meiotic chromosome structure and recombination.

KEYWORDS:

AAA+ ATPase; C. elegans; HORMA domain protein; biochemistry; biophysics; mouse; spindle assembly checkpoint; structural biology

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PMID:
25918846
PMCID:
PMC4439613
DOI:
10.7554/eLife.07367
[Indexed for MEDLINE]
Free PMC Article

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