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Cell Cycle. 2016;15(8):1117-24. doi: 10.1080/15384101.2016.1158362.

Structure of the human dimeric ATM kinase.

Author information

1
a School of Biomedical Sciences, The University of Hong Kong , Hong Kong.
2
b State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong , Hong Kong.
3
c State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou , China.
4
d Guangdong Provincial Center for Disease Control and Prevention , Guangzhou , China.

Abstract

DNA-double strand breaks activate the serine/threonine protein kinase ataxia-telangiectasia mutated (ATM) to initiate DNA damage signal transduction. This activation process involves autophosphorylation and dissociation of inert ATM dimers into monomers that are catalytically active. Using single-particle electron microscopy (EM), we determined the structure of dimeric ATM in its resting state. The EM map could accommodate the crystal structure of the N-terminal truncated mammalian target of rapamycin (mTOR), a closely related enzyme of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family, allowing for the localization of the N- and the C-terminal regions of ATM. In the dimeric structure, the actives sites are buried, restricting the access of the substrates to these sites. The unanticipated domain organization of ATM provides a basis for understanding its mechanism of inhibition.

KEYWORDS:

ATM kinase; DNA damage; DNA damage response; PIKK; ataxia telangiectasia; electron microscopy (EM); post-translational modification (PTM)

PMID:
27097373
PMCID:
PMC4889239
DOI:
10.1080/15384101.2016.1158362
[Indexed for MEDLINE]
Free PMC Article

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