Cryo-EM structure of human ATR-ATRIP complex
Cryo-EM structure of human ATR-ATRIP complex
复制标题
人 ATR-ATRIP 复合物的冷冻电镜结构。
DOI：
10.1038/cr.2017.158
复制
发表时间：
2018-02-01
期刊：
影响因子：
44.1
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Rao, Qinhui;Liu, Mengjie;Xu, Yanhui
ATR(共济失调毛细血管扩张突变和RAD3相关)蛋白激酶和ATIP(ATR相互作用蛋白)形成一个复合体，在应对复制应激和DNA损伤中发挥关键作用。在这里，我们测定了4.7埃分辨率的人ATR-AIP复合体的冷冻电子显微镜(EM)结构，并建立了3.9埃分辨率的ATR(残基1 521-2 644)的C末端催化核心的原子模型。该络合物呈中空的“心”形，由两个不同构象的ATR单体组成。ARip的EM图显示了14个热重复，呈延伸的“S”形状。ATR的构象灵活性使ATAP能够适当地锁定两个ATR单体的N-末端，从而有利于ATR-ATIP复合体的形成和功能的多样性。孤立的“头-头”和“尾-尾”各自采用了一种伪2重对称。催化腔朝外，底物访问不受抑制元素的限制。我们的研究为理解ATR-ATrip复合体的组装提供了结构基础，并为表征ATR介导的DNA修复途径提供了一个框架。
ATR (ataxia telangiectasia-mutated and Rad3-related) protein kinase and ATRIP (ATR-interacting protein) form a complex and play a critical role in response to replication stress and DNA damage. Here, we determined the cryo-electron microscopy (EM) structure of the human ATR-ATRIP complex at 4.7 angstrom resolution and built an atomic model of the C-terminal catalytic core of ATR (residues 1 521-2 644) at 3.9 angstrom resolution. The complex adopts a hollow "heart" shape, consisting of two ATR monomers in distinct conformations. The EM map for ATRIP reveals 14 HEAT repeats in an extended "S" shape. The conformational flexibility of ATR allows ATRIP to properly lock the N-termini of the two ATR monomers to favor ATR-ATRIP complex formation and functional diversity. The isolated "head-head" and "tail-tail" each adopts a pseudo 2-fold symmetry. The catalytic pockets face outward and substrate access is not restricted by inhibitory elements. Our studies provide a structural basis for understanding the assembly of the ATR-ATRIP complex and a framework for characterizing ATR-mediated DNA repair pathways.