The Immune Disease Institute, Children's Hospital Boston, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21010-5. doi: 10.1073/pnas.1113651108. Epub 2011 Dec 12.
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.
MDA5 是一种 RIG-I 样解旋酶，作为一种保守的细胞质病毒 RNA 传感器，它以依赖于长度的方式识别来自广泛病毒的 dsRNA。据推测，MDA5 在病毒 dsRNA 识别或抗病毒信号转导过程中形成更高阶的结构，然而，这种提议的寡聚状态的组织和性质尚不清楚。我们在此报告，MDA5 合作组装成一种丝状寡聚物，由沿着 dsRNA 长度排列的 MDA5 二聚体的重复片段排列组成。MDA5 与 dsRNA 的结合刺激其 ATP 水解活性，而丝状分子内相邻分子之间的协调作用很小。单个 ATP 水解反过来使 MDA5 丝的内在动力学不稳定性，以与丝状长度成反比的速率触发 MDA5 从 dsRNA 解离。这些结果表明，ATP 水解在控制丝状组装和拆卸过程中发挥了以前未被认识的作用，从而自动调节 MDA5 与 dsRNA 的相互作用，并为 dsRNA 长度依赖性抗病毒信号转导提供了潜在的基础。
