title: Structure of the intact ATM/Tel1 kinase.
abstract: The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.
authors.affiliation: Key Laboratory of Agricultural and Environmental Microbiology, Ministry of Agriculture, College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China.|School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Xuejuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Chu
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Mengjuan
authors.initials: M
authors.lastname: Lv
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Shuwan
authors.initials: S
authors.lastname: Qiu
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA.
authors.forename: Xuetong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Key Laboratory of Agricultural and Environmental Microbiology, Ministry of Agriculture, College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China.
authors.forename: Weiwu
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at the Microscale, Center for Integrative Imaging, Anhui 230027, China.|Center for Biomedical Engineering, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Cai
mesh_terms: D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D020285:Cryoelectron Microscopy; D008958:Models, Molecular; D011487:Protein Conformation; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D029702:Schizosaccharomyces pombe Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C513624:tel1 protein, S pombe