Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition |
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Authors: | Peisley Alys Lin Cecilie Wu Bin Orme-Johnson McGhee Liu Mengyuan Walz Thomas Hur Sun |
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Affiliation: | The Immune Disease Institute, Children's Hospital Boston, Boston, MA 02115, USA. |
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Abstract: | 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. |
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Keywords: | pattern recognition receptor receptor clustering dynamic instability |
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