Journal
CELL CYCLE
Volume 15, Issue 8, Pages 1117-1124Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2016.1158362
Keywords
ATM kinase; ataxia telangiectasia; DNA damage response; DNA damage; electron microscopy (EM); PIKK; post-translational modification (PTM)
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Funding
- Research Grants Council Hong Kong - Early Career Scheme [786512]
- AXA Research Fund fellowship
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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.
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