Structures of closed and open conformations of dimeric human ATM.
Structures of closed and open conformations of dimeric human ATM.
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DOI：
10.1126/sciadv.1700933
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发表时间：
2017-05
期刊：
影响因子：
13.6
通讯作者：
Williams RL
中科院分区：
文献类型：
--
作者：
Baretić D;Pollard HK;Fisher DI;Johnson CM;Santhanam B;Truman CM;Kouba T;Fersht AR;Phillips C;Williams RL
电子冷冻显微镜表明，ATM是通过开放和闭合二聚体之间的动态平衡来调节的。ATM(共济失调-毛细血管扩张症突变)是一种磷脂酰肌醇3-激酶相关蛋白激酶(Pikk)，因其在DNA损伤反应中的作用而闻名。ATM还在氧化应激反应、胰岛素信号转导和神经发生中发挥作用。我们的电子冷冻显微镜(Cryo-EM)表明，人类ATM处于闭合和开放二聚体之间的动态平衡。在关闭状态下，Pikk调节域阻止了多肽底物结合部位，这表明这种构象可能代表了一种失活或碱性活性的酶。通过与对称相关分子的TRD3(四肽重复结构域3)结构域中的长螺旋发夹相互作用，活性中心被保持在这种封闭的构象中。开放二聚体有两个原基，只有有限的接触界面，并且它缺乏分子间的相互作用，而分子间相互作用阻止了闭合二聚体中的肽结合部位。这表明开放构象可能更活跃。ATM结构显示了调节器相互作用的N端螺旋螺线管的详细拓扑结构。这些结构所显示的ATM构象动力学代表了理解酶调节的重要一步。
Electron cryomicroscopy suggests regulation of ATM by a dynamic equilibrium between open and closed dimers. ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase–related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. In the closed state, the PIKK regulatory domain blocks the peptide substrate–binding site, suggesting that this conformation may represent an inactive or basally active enzyme. The active site is held in this closed conformation by interaction with a long helical hairpin in the TRD3 (tetratricopeptide repeats domain 3) domain of the symmetry-related molecule. The open dimer has two protomers with only a limited contact interface, and it lacks the intermolecular interactions that block the peptide-binding site in the closed dimer. This suggests that the open conformation may be more active. The ATM structure shows the detailed topology of the regulator-interacting N-terminal helical solenoid. The ATM conformational dynamics shown by the structures represent an important step in understanding the enzyme regulation.