期刊
CELLULAR SIGNALLING
卷 26, 期 9, 页码 1825-1836出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.05.004
关键词
Chk2; Checkpoint kinase 2; CHEK2
类别
资金
- Canadian Institutes of Health Research [MOP36399, MOP89754, MOP12859]
- Canada Research Chairs
- Thomas Kierans Chair in Molecular Mechanisms of Cancer
The protein kinase Rad53 is a key regulator of the DNA damage checkpoint in budding yeast. Its human ortholog, CHEK2, is mutated in familial breast cancer and mediates apoptosis in response to genotoxic stress. Autophosphorylation of Rad53 at residue Thr354 located in the kinase activation segment is essential for Rad53 activation. In this study, we assessed the requirement of kinase domain dimerization and the exchange of its activation segment during the Rad53 activation process. We solved the crystal structure of Rad53 in its dimeric form and found that disruption of the observed head-to-tail, face-to-face dimer structure decreased Rad53 autophosphorylation on Thr354 in vitro and impaired Rad53 function in vivo. Moreover, we provide critical functional evidence that Rad53 trans-autophosphorylation may involve the interkinase domain exchange of helix alpha EF via an invariant salt bridge. These findings suggest a mechanism of autophosphorylation that may be broadly applicable to other protein kinases. (C) 2014 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据