Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition
Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition
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DOI：
10.1073/pnas.1113651108
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发表时间：
2011-12-27
影响因子：
11.1
通讯作者：
Hur, Sun
中科院分区：
文献类型：
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作者：
Peisley, Alys;Lin, Cecilie;Hur, Sun
MDA 5是一种RIG-I样解旋酶，是一种保守的细胞质病毒RNA传感器，它以长度依赖的方式识别来自广泛病毒的dsRNA。已经提出，MDA 5在病毒dsRNA识别或抗病毒信号传导期间形成更高级的结构，然而这种提出的寡聚状态的组织和性质是未知的。我们在这里报告，MDA 5合作组装成一个丝状寡聚体组成的MDA 5二聚体的重复节段排列沿着dsRNA的长度。MDA 5与dsRNA的结合刺激其ATP水解活性，而细丝内相邻分子之间几乎没有配位。单独的ATP水解反过来又使MDA 5细丝具有内在的动力学不稳定性，触发MDA 5以与细丝长度成反比的速率从dsRNA解离。这些结果表明ATP水解在控制细丝组装和拆卸过程中的先前未被认识的作用，从而自动调节MDA 5与dsRNA的相互作用，并为dsRNA长度依赖性抗病毒信号传导提供了潜在的基础。
MDA5, an RIG-I-like helicase, is a conserved cytoplasmic viral RNA sensor, which recognizes dsRNA from a wide-range of viruses in a length-dependent manner. It has been proposed that MDA5 forms higher-order structures upon viral dsRNA recognition or during antiviral signaling, however the organization and nature of this proposed oligomeric state is unknown. We report here that MDA5 cooperatively assembles into a filamentous oligomer composed of a repeating segmental arrangement of MDA5 dimers along the length of dsRNA. Binding of MDA5 to dsRNA stimulates its ATP hydrolysis activity with little coordination between neighboring molecules within a filament. Individual ATP hydrolysis in turn renders an intrinsic kinetic instability to the MDA5 filament, triggering dissociation of MDA5 from dsRNA at a rate inversely proportional to the filament length. These results suggest a previously unrecognized role of ATP hydrolysis in control of filament assembly and disassembly processes, thereby autoregulating the interaction of MDA5 with dsRNA, and provides a potential basis for dsRNA length-dependent antiviral signaling.