Structure of the human dimeric ATM kinase

作者：Wilson Chun Yu Lau, Yinyin Li, Zhe Liu, Yuanzhu Gao, Qinfen Zhang, Michael S.Y. Huen · 发表于：Cell Cycle · 年份：2016 · DOI：10.1080/15384101.2016.1158362 · 被引用次数：53 · 研究领域：DNA Repair Mechanisms、Advanced Electron Microscopy Techniques and Applications、Cancer therapeutics and mechanisms

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.