Structure of the intact ATM/Tel1 kinase

Xuejuan Wang, Huanyu Chu, Mengjuan Lv, Zhihui Zhang, Shuwan Qiu, Haiyan Liu, Xuetong Shen, Weiwu Wang () and Gang Cai ()
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Xuejuan Wang: Key Laboratory of Agricultural and Environmental Microbiology, Ministry of Agriculture, College of Life Sciences, Nanjing Agricultural University
Huanyu Chu: School of Life Sciences, University of Science and Technology of China
Mengjuan Lv: School of Life Sciences, University of Science and Technology of China
Zhihui Zhang: School of Life Sciences, University of Science and Technology of China
Shuwan Qiu: School of Life Sciences, University of Science and Technology of China
Haiyan Liu: School of Life Sciences, University of Science and Technology of China
Xuetong Shen: University of Texas M.D. Anderson Cancer Center
Weiwu Wang: Key Laboratory of Agricultural and Environmental Microbiology, Ministry of Agriculture, College of Life Sciences, Nanjing Agricultural University
Gang Cai: School of Life Sciences, University of Science and Technology of China

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11655

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