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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1
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Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1

机译：人寡聚腺苷酸合成酶1监测胞质双链RNA的结构基础

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摘要

The human sensor of double-stranded RNA (dsRNA) oligoadenylate synthetase 1 (hOAS1) polymerizes ATP into 2,5 -linked iso-RNA (2-5A) involved in innate immunity, cell cycle, and differentiation. We report the crystal structure of hOAS1 in complex with dsRNA and 2-deoxy ATP at 2.7 A resolution, which reveals the mechanism of cytoplasmic dsRNA recognition and activation of oligoadenylate synthetases. Human OAS1 recognizes dsRNA using a previously uncharacterized protein/RNA interface that forms via a conforma-tional change induced by binding of dsRNA. The protein/RNA interface involves two minor grooves and has no sequence-specific contacts, with the exception of a single hydrogen bond between the -NH_2 group of nucleobase G17 and the carbonyl oxygen of serine 56. Using a biochemical readout, we show that hOAS1 undergoes more than 20,000-fold activation upon dsRNA binding and that canonical or GU-wobble substitutions produce dsRNA mutants that retain either full or partial activity, in agreement with the crystal structure. Ultimately, the binding of dsRNA promotes an elaborate conformational rearrangement in the N-terminal lobe of hOAS1, which brings residues D75, D77, and D148 into proximity and creates coordination geometry for binding of two catalytic Mg~(2+) ions and ATP. The assembly of this critical active-site structure provides the gate that couples binding of dsRNA to the production and downstream functions of 2-5A.
机译：人类双链RNA（dsRNA）寡腺苷酸合成酶1（hOAS1）的传感器将ATP聚合成2,5连接的异RNA（2-5A），涉及先天免疫，细胞周期和分化。我们报告了在2.7 A分辨率下与dsRNA和2-deoxy ATP结合的hOAS1的晶体结构，揭示了胞质dsRNA识别和寡聚腺苷酸合成酶激活的机制。人类OAS1使用以前未表征的蛋白质/ RNA界面识别dsRNA，该界面是通过dsRNA结合诱导的构象变化形成的。蛋白质/ RNA界面涉及两个小沟，没有序列特异性接触，但碱基G17的-NH_2基团与丝氨酸56的羰基氧之间只有一个氢键。使用生化读数，我们发现hOAS1在dsRNA结合后经历超过20,000倍的激活，并且规范或GU摆动取代产生的dsRNA突变体保留全部或部分活性，与晶体结构一致。最终，dsRNA的结合促进了hOAS1 N末端叶的精细构象重排，使残基D75，D77和D148接近并形成了两个几何Mg〜（2+）离子和ATP结合的配位几何。该关键活性位点结构的组装提供了将dsRNA结合与2-5A产生和下游功能结合的门。

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