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Nat Commun. 2016 May 27;7:11655. doi: 10.1038/ncomms11655.

Structure of the intact ATM/Tel1 kinase.

Author information

1
Key Laboratory of Agricultural and Environmental Microbiology, Ministry of Agriculture, College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China.
2
School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
3
Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA.
4
Hefei National Laboratory for Physical Sciences at the Microscale, Center for Integrative Imaging, Anhui 230027, China.
5
Center for Biomedical Engineering, University of Science and Technology of China, Anhui 230027, China.

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.

PMID:
27229179
PMCID:
PMC4894967
DOI:
10.1038/ncomms11655
[Indexed for MEDLINE]
Free PMC Article

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