Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5
Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5
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DOI：
10.1016/j.abb.2009.06.008
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发表时间：
2009-08-01
影响因子：
3.9
通讯作者：
Li, Pingwei
中科院分区：
文献类型：
--
作者：
Li, Xiaojun;Lu, Cheng;Li, Pingwei
RIG-I、MIDA5 和 LGP2 是胞质模式识别受体，可检测病毒感染细胞中的单链或双链 RNA。 RIG-I 或 MDA5 的激活会刺激 I 型干扰素的分泌，而 I 型干扰素在抗病毒免疫反应中发挥关键作用。 RIG-I 和 LGP2 的 C 端结构域 (CTD) 负责 RNA 结合；然而，目前尚不清楚MDA5如何结合RNA。为了了解 MDA5 识别 dsRNA 的结构基础，我们确定了人 MDA5 C 端结构域的 1.45 埃分辨率结构。该结构显示出高度保守的折叠，类似于 RIG-I 和 LGP2 CTD 的结构。用 dsRNA 对 MDA5 CTD 进行 NMR 滴定证明带正电荷的表面参与 dsRNA 结合。诱变和 RNA 结合研究表明静电相互作用在 MDA5 识别 dsRNA 中起主要作用。与 RIG-I 和 LGP2 一样，MDA5 CTD 优先结合具有平端的 dsRNA，但不与具有 5' 或 3' 突出端的 dsRNA 结合。 MIDA5 CTD/dsRNA 复合物的分子模型表明，MDA5 CTD 可能以与 LGP2 类似的方式识别平端 dsRNA 的第一转。由爱思唯尔公司出版
RIG-I, MIDA5 and LGP2 are cytosolic pattern recognition receptors detecting single-stranded or double-stranded RNA in virally infected cells. The activation of RIG-I or MDA5 stimulates the secretion of type I interferons that play key roles in antiviral immune responses. The C-terminal domains (CTD) of RIG-I and LGP2 are responsible for RNA binding; however, it is not clear how MDA5 binds RNA. To understand the structural basis of dsRNA recognition by MDA5, we have determined the 1.45 angstrom resolution structure of the C-terminal domain of human MDA5. The structure revealed a highly conserved fold similar to the Structures of RIG-I and LGP2 CTDs. NMR titration of MDA5 CTD with dsRNA demonstrated that a positively charged surface is involved in dsRNA binding. Mutagenesis and RNA binding studies showed that electrostatic interactions play primary roles in dsRNA recognition by MDA5. Like RIG-I and LGP2, MDA5 CTD preferentially binds dsRNA with blunt ends, but does not associate with dsRNA with either 5' or 3' overhangs. Molecular modeling of MIDA5 CTD/dsRNA complex suggests that MDA5 CTD may recognize the first turn of blunt-ended dsRNA in a similar manner as LGP2. Published by Elsevier Inc.