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Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes.

Abstract：

:The AAA-ATPase thyroid hormone receptor interacting protein 13 (TRIP13), jointly with the Mad2-binding protein p31(comet), promotes the inactivation of the mitotic (spindle assembly) checkpoint by disassembling the mitotic checkpoint complex (MCC). This checkpoint system ensures the accuracy of chromosome segregation by delaying anaphase until correct bipolar attachment of chromatids to the mitotic spindle is achieved. MCC inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation securin, an inhibitor of anaphase initiation. MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3, in association with the APC/C activator Cdc20. The assembly of MCC in active checkpoint is initiated by the conversion of Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformation, which then binds tightly to Cdc20. Conversely, the disassembly of MCC that takes place when the checkpoint is turned off involves the conversion of C-Mad2 back to O-Mad2. Previously, we found that the latter process is mediated by TRIP13 together with p31(comet), but the mode of their interaction remained unknown. Here, we report that the oligomeric form of TRIP13 binds both p31(comet) and MCC. Furthermore, p31(comet) and checkpoint complexes mutually promote the binding of each other to oligomeric TRIP13. We propose that p31(comet) bound to C-Mad2-containing checkpoint complex is the substrate for the ATPase and that the substrate-binding site of TRIP13 is composed of subsites specific for p31(comet) and C-Mad2-containing complex. The simultaneous occupancy of both subsites is required for high-affinity binding to TRIP13.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Miniowitz-Shemtov S,Eytan E,Kaisari S,Sitry-Shevah D,Hershko A

doi

10.1073/pnas.1515358112

subject

Has Abstract

pub_date

2015-09-15 00:00:00

pages

11536-40

issue

eissn

0027-8424

issn

1091-6490

pii

1515358112

journal_volume

112

pub_type

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Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes.