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.
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, United States.
Qiaozhen
Q
Ye
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, United States.
Scott C
SC
Rosenberg
National Resource for Automated Molecular Microscopy, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States.
Arne
A
Moeller
National Resource for Automated Molecular Microscopy, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States.
Jeffrey A
JA
Speir
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, United States.
Tiffany Y
TY
Su
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, United States.
Kevin D
http://orcid.org/0000-0001-5854-2388
KD
Corbett
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000145:classification / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D049071:Endopeptidase Clp / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D008941:Spindle Apparatus / Q000201:enzymology* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029968:Escherichia coli Proteins; C576915:HORMAD1 protein, human; C577697:MAD2L1 protein, human; C470309:MAD2L1BP protein, human; D064246:Mad2 Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C000599595:PCH-2 protein, C elegans; D011994:Recombinant Proteins; D049071:Endopeptidase Clp; D000251:Adenosine Triphosphatases; C404942:p97 ATPase; C088072:ClpX protein, E coli; D000074183:ATPases Associated with Diverse Cellular Activities; C575259:TRIP13 protein, human; D052066:N-Ethylmaleimide-Sensitive Proteins
AAA+ ATPase; C. elegans; HORMA domain protein; biochemistry; biophysics; mouse; spindle assembly checkpoint; structural biology