The Activation Mechanism of 2′-5′-Oligoadenylate Synthetase Gives New Insights Into OAS/cGAS Triggers of Innate Immunity
The Activation Mechanism of 2′-5′-Oligoadenylate Synthetase Gives New Insights Into OAS/cGAS Triggers of Innate Immunity
复制标题
DOI：
10.1016/j.str.2015.03.012
复制
发表时间：
2015-05-05
期刊：
影响因子：
5.7
通讯作者：
Fedorov, Roman
中科院分区：
文献类型：
--
作者：
Lohoefener, Jan;Steinke, Nicola;Fedorov, Roman
2 '-5'-寡腺苷酸合成酶（OAS）产生第二信使2 '-5'-寡腺苷酸，其激活RNA酶L以诱导内在抗病毒状态。我们报告OAS 1的催化中间体的晶体结构，包括OAS1.dsRNA复合物没有基板，与供体基板，并与供体和受体基板。结合点突变体的动力学研究和先前发表的OAS 1的载脂蛋白形式的结构，新的数据表明了OAS激活的顺序机制，并显示了每个组件的单独作用。他们揭示了dsRNA介导的推拉效应，负责OAS 1中的大构象变化，活性位点Mg 2+的催化作用，以及产物形成的2 '特异性的结构基础。我们的数据揭示了天然免疫传感器的OAS/环GMP-AMP合酶家族成员的激活机制的相似性和差异。特别是，他们显示了螺旋3（10）3-α 5如何阻止OAS 1合成环状二核苷酸。
2'-5'-Oligoadenylate synthetases (OASs) produce the second messenger 2'-5'-oligoadenylate, which activates RNase L to induce an intrinsic antiviral state. We report on the crystal structures of catalytic intermediates of OAS1 including the OAS1.dsRNA complex without substrates, with a donor substrate, and with both donor and acceptor substrates. Combined with kinetic studies of point mutants and the previously published structure of the apo form of OAS1, the new data suggest a sequential mechanism of OAS activation and show the individual roles of each component. They reveal a dsRNA-mediated push-pull effect responsible for large conformational changes in OAS1, the catalytic role of the active site Mg2+, and the structural basis for the 2'-specificity of product formation. Our data reveal similarities and differences in the activation mechanisms of members of the OAS/cyclic GMP-AMP synthase family of innate immune sensors. In particular, they show how helix 3(10)3-alpha 5 blocks the synthesis of cyclic dinucleotides by OAS1.