Phosphatidylinositol 3-kinase-related kinases (PIKKs) are composed of conserved FAT and kinase domains (FATKIN) along with varied solenoid structures made of HEAT repeats. These kinases are activated in response to cellular stress signals, but the mechanisms governing activation and regulation remain unresolved. For DNA-dependent protein kinase (DNA-PK), all existing structures represent inactive states with resolution limited to 4.3 angstrom at best. Here we report the cryoEM structures of DNA-PKcs (catalytic subunit) bound to a DNA end, or complexed with Ku70/80 and DNA, in both inactive and activated forms at resolutions of 3.7 angstrom overall, and 3.2 angstrom for FATKIN. These structures reveal the sequential transition of DNA-PK from inactive to activated forms. Most notably, activation of the kinase involves previously unknown stretching and twisting within individual solenoid segments and coordinated shifts of neighboring segments in opposite directions. This unprecedented structural plasticity of helical repeats may be a general feature of HEAT-repeat proteins.

中文翻译：

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HEAT的拉伸和扭曲重复导致DNA-PK激酶激活

磷脂酰肌醇3-激酶相关的激酶（PIKK）由保守的FAT和激酶结构域（FATKIN）以及由HEAT重复组成的各种螺线管结构组成。这些激酶响应细胞应激信号而被激活，但是控制激活和调节的机制仍未解决。对于依赖DNA的蛋白激酶（DNA-PK），所有现有结构均表示非活性状态，其分辨率最高限制为4.3埃。在这里，我们报告的DNA-PKcs（催化亚基）的cryoEM结构与DNA末端结合或与Ku70 / 80和DNA形成复合物，呈非活性形式和活化形式，总分辨率为3.7埃，FATKIN的分辨率为3.2埃。这些结构揭示了DNA-PK从无活性形式到活化形式的顺序转变。最为显着地，激酶的激活涉及单个螺线管片段内先前未知的拉伸和扭曲以及相邻片段在相反方向上的协调移位。螺旋重复序列的这种前所未有的结构可塑性可能是HEAT重复蛋白的普遍特征。