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Title: The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding

Abstract

Proteins of the conserved HORMA domain family, including the spindle assembly checkpoint protein MAD2 and the meiotic HORMADs, assemble into signaling complexes by binding short peptides termed “closure motifs”. The AAA+ ATPase TRIP13 regulates both MAD2 and meiotic HORMADs by disassembling these HORMA domain–closure motif complexes, but its mechanisms of substrate recognition and remodeling are unknown. Here, we combine X-ray crystallography and crosslinking mass spectrometry to outline how TRIP13 recognizes MAD2 with the help of the adapter protein p31comet. We show that p31comet binding to the TRIP13 N-terminal domain positions the disordered MAD2 N-terminus for engagement by the TRIP13 “pore loops”, which then unfold MAD2 in the presence of ATP. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro, and in cells causes spindle assembly checkpoint defects consistent with loss of TRIP13 function. Similar truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13-mediated removal from meiotic chromosomes, highlighting a conserved mechanism for recognition and disassembly of HORMA domain–closure motif complexes by TRIP13.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER
OSTI Identifier:
1390878
Resource Type:
Journal Article
Resource Relation:
Journal Name: EMBO Journal; Journal Volume: 36; Journal Issue: 16
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Ye, Qiaozhen, Kim, Dong Hyun, Dereli, Ihsan, Rosenberg, Scott C., Hagemann, Goetz, Herzog, Franz, Tóth, Attila, Cleveland, Don W., and Corbett, Kevin D. The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding. United States: N. p., 2017. Web. doi:10.15252/embj.201797291.
Ye, Qiaozhen, Kim, Dong Hyun, Dereli, Ihsan, Rosenberg, Scott C., Hagemann, Goetz, Herzog, Franz, Tóth, Attila, Cleveland, Don W., & Corbett, Kevin D. The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding. United States. doi:10.15252/embj.201797291.
Ye, Qiaozhen, Kim, Dong Hyun, Dereli, Ihsan, Rosenberg, Scott C., Hagemann, Goetz, Herzog, Franz, Tóth, Attila, Cleveland, Don W., and Corbett, Kevin D. Wed . "The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding". United States. doi:10.15252/embj.201797291.
@article{osti_1390878,
title = {The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding},
author = {Ye, Qiaozhen and Kim, Dong Hyun and Dereli, Ihsan and Rosenberg, Scott C. and Hagemann, Goetz and Herzog, Franz and Tóth, Attila and Cleveland, Don W. and Corbett, Kevin D.},
abstractNote = {Proteins of the conserved HORMA domain family, including the spindle assembly checkpoint protein MAD2 and the meiotic HORMADs, assemble into signaling complexes by binding short peptides termed “closure motifs”. The AAA+ ATPase TRIP13 regulates both MAD2 and meiotic HORMADs by disassembling these HORMA domain–closure motif complexes, but its mechanisms of substrate recognition and remodeling are unknown. Here, we combine X-ray crystallography and crosslinking mass spectrometry to outline how TRIP13 recognizes MAD2 with the help of the adapter protein p31comet. We show that p31comet binding to the TRIP13 N-terminal domain positions the disordered MAD2 N-terminus for engagement by the TRIP13 “pore loops”, which then unfold MAD2 in the presence of ATP. N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro, and in cells causes spindle assembly checkpoint defects consistent with loss of TRIP13 function. Similar truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13-mediated removal from meiotic chromosomes, highlighting a conserved mechanism for recognition and disassembly of HORMA domain–closure motif complexes by TRIP13.},
doi = {10.15252/embj.201797291},
journal = {EMBO Journal},
number = 16,
volume = 36,
place = {United States},
year = {Wed Jun 28 00:00:00 EDT 2017},
month = {Wed Jun 28 00:00:00 EDT 2017}
}