Structure of the human dimeric ATM kinase.
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.
a School of Biomedical Sciences, The University of Hong Kong , Hong Kong.|b State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong , Hong Kong.
Wilson C Y
WC
Lau
c State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou , China.
Yinyin
Y
Li
d Guangdong Provincial Center for Disease Control and Prevention , Guangzhou , China.
Zhe
Z
Liu
c State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou , China.
Yuanzhu
Y
Gao
c State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou , China.
Qinfen
Q
Zhang
a School of Biomedical Sciences, The University of Hong Kong , Hong Kong.|b State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong , Hong Kong.
Michael S Y
MS
Huen
D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008958:Models, Molecular; D010084:Oxidation-Reduction; D055503:Protein Multimerization; D021122:Protein Subunits / Q000378:metabolism
D021122:Protein Subunits; D064007:Ataxia Telangiectasia Mutated Proteins
ATM kinase; DNA damage; DNA damage response; PIKK; ataxia telangiectasia; electron microscopy (EM); post-translational modification (PTM)