title: Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition.
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.
authors.affiliation: The Immune Disease Institute, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Alys
authors.initials: A
authors.lastname: Peisley
authors.forename: Cecilie
authors.initials: C
authors.lastname: Lin
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: McGhee
authors.initials: M
authors.lastname: Orme-Johnson
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Sun
authors.initials: S
authors.lastname: Hur
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004586:Electrophoresis / Q000379:methods; D004686:Encephalomyocarditis virus / Q000235:genetics; D006801:Humans; D006868:Hydrolysis; D007091:Image Processing, Computer-Assisted; D000072640:Interferon-Induced Helicase, IFIH1; D008574:Mengovirus / Q000235:genetics; D008854:Microscopy, Electron; D020125:Mutation, Missense / Q000235:genetics; D011487:Protein Conformation; D012330:RNA, Double-Stranded / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051192:Receptors, Pattern Recognition; D000255:Adenosine Triphosphate; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1