3.9 Å structure of the yeast Mec1-Ddc2 complex, a homolog of human ATR-ATRIP

被引：52

作者：

Wang, Xuejuan ^{[1
,2
,3
]}

Ran, Tingting ^{[4
]}

Zhang, Xuan ^{[1
,2
]}

Xin, Jiyu ^{[1
,2
]}

Zhang, Zhihui ^{[1
,2
]}

Wu, Tengwei ^{[1
,2
]}

Wang, Weiwu ^{[4
]}

Cai, Gang ^{[1
,2
,3
]}

机构：

[1] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China

[2] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China

[3] Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Hefei 230026, Anhui, Peoples R China

[4] Nanjing Agr Univ, Key Lab Agr & Environm Microbiol, Minist Agr, Coll Life Sci, Nanjing 210095, Jiangsu, Peoples R China

来源：

SCIENCE | 2017年 / 358卷 / 6367期

基金：

中国国家自然科学基金;

关键词：

STALLED REPLICATION FORKS; ATAXIA-TELANGIECTASIA; CHECKPOINT ACTIVATION; DNA-DAMAGE; PROTEIN; KINASE; ARCHITECTURE; MEC1(ATR);

D O I：

10.1126/science.aan8414

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans, but the mechanism of its activation remains unclear. ATR acts together with its partner ATRIP. Using cryo-electron microscopy, we determined the structure of intact Mec1-Ddc2 (the yeast homolog of ATR-ATRIP), which is poised for catalysis, at a resolution of 3.9 angstroms. Mec1-Ddc2 forms a dimer of heterodimers through the PRD and FATdomains of Mec1 and the coiled-coil domain of Ddc2. The PRD and Bridge domains in Mec1 constitute critical regulatory sites. The activation loop of Mec1 is inhibited by the PRD, revealing an allosteric mechanism of kinase activation. Our study clarifies the architecture of ATR-ATRIP and provides a structural framework for the understanding of ATR regulation.

引用

页码：1206 / 1209

页数：4

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