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

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.
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [1] ; ORCiD logo [3]
  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
  3. Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, United States, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
Publication Date:
Type:
Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 4; Related Information: CHORUS Timestamp: 2017-10-18 18:25:10; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
OSTI Identifier:
1182456
Alternate Identifier(s):
OSTI ID: 1228260