Cryo-EM structure of human ATR-ATRIP complex
| Autor: | Qinhui Rao, Mengjie Liu, Yuan Tian, Zihan Wu, Yuhan Hao, Lei Song, Zhaoyu Qin, Chen Ding, Hong-Wei Wang, Jiawei Wang, Yanhui Xu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Protein Conformation alpha-Helical Protein Folding Ataxia Telangiectasia Mutated Proteins Chromatography Affinity 03 medical and health sciences 0302 clinical medicine stomatognathic system Humans Phosphorylation Molecular Biology Adaptor Proteins Signal Transducing TOR Serine-Threonine Kinases Cryoelectron Microscopy Nuclear Proteins Cell Biology Isoxazoles DNA-Binding Proteins 030104 developmental biology 030220 oncology & carcinogenesis Pyrazines Mutation Chromatography Gel Original Article biological phenomena cell phenomena and immunity Protein Multimerization Carrier Proteins Protein Kinases DNA Damage Protein Binding Signal Transduction |
| Zdroj: | Cell research. 28(2) |
| ISSN: | 1748-7838 |
| Popis: | 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 Å resolution and built an atomic model of the C-terminal catalytic core of ATR (residues 1 521-2 644) at 3.9 Å 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. |
| Databáze: | OpenAIRE |
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