Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
Science. 2013 Feb 8;339(6120):690-3. doi: 10.1126/science.1230949. Epub 2013 Jan 17.
The retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) melanoma differentiation-associated protein 5 (MDA5) senses cytoplasmic viral RNA and activates antiviral innate immunity. To reveal how paramyxoviruses counteract this response, we determined the crystal structure of the MDA5 adenosine 5'-triphosphate (ATP)-hydrolysis domain in complex with the viral inhibitor V protein. The V protein unfolded the ATP-hydrolysis domain of MDA5 via a β-hairpin motif and recognized a structural motif of MDA5 that is normally buried in the conserved helicase fold. This leads to disruption of the MDA5 ATP-hydrolysis site and prevention of RNA-bound MDA5 filament formation. The structure explains why V proteins inactivate MDA5, but not RIG-I, and mutating only two amino acids in RIG-I induces robust V protein binding. Our results suggest an inhibition mechanism of RLR signalosome formation by unfolding of receptor and inhibitor.
视黄酸诱导基因 I（RIG-I）样受体（RLR）黑色素瘤分化相关蛋白 5（MDA5）感知细胞质中的病毒 RNA 并激活抗病毒先天免疫。为了揭示副粘病毒如何对抗这种反应，我们确定了 MDA5 腺苷 5'-三磷酸（ATP）水解结构域与病毒抑制剂 V 蛋白复合物的晶体结构。V 蛋白通过 β-发夹模体展开 MDA5 的 ATP 水解结构域，并识别 MDA5 中通常埋藏在保守解旋酶折叠中的结构模体。这导致 MDA5 ATP 水解位点的破坏和阻止 RNA 结合的 MDA5 丝状体形成。该结构解释了为什么 V 蛋白使 MDA5 失活，但不使 RIG-I 失活，并且仅在 RIG-I 中突变两个氨基酸就会诱导强烈的 V 蛋白结合。我们的结果表明，通过受体和抑制剂的展开来抑制 RLR 信号小体的形成的抑制机制。
