title: Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5.
abstract: MDA5, a viral double-stranded RNA (dsRNA) receptor, shares sequence similarity and signaling pathways with RIG-I yet plays essential functions in antiviral immunity through distinct specificity for viral RNA. Revealing the molecular basis for the functional divergence, we report here the crystal structure of MDA5 bound to dsRNA, which shows how, using the same domain architecture, MDA5 recognizes the internal duplex structure, whereas RIG-I recognizes the terminus of dsRNA. We further show that MDA5 uses direct protein-protein contacts to stack along dsRNA in a head-to-tail arrangement, and that the signaling domain (tandem CARD), which decorates the outside of the core MDA5 filament, also has an intrinsic propensity to oligomerize into an elongated structure that activates the signaling adaptor, MAVS. These data support a model in which MDA5 uses long dsRNA as a signaling platform to cooperatively assemble the core filament, which in turn promotes stochastic assembly of the tandem CARD oligomers for signaling.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Alys
authors.initials: A
authors.lastname: Peisley
authors.forename: Claire
authors.initials: C
authors.lastname: Richards
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zeng
authors.forename: Cecilie
authors.initials: C
authors.lastname: Lin
authors.forename: Feixia
authors.initials: F
authors.lastname: Chu
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Sun
authors.initials: S
authors.lastname: Hur
mesh_terms: D000595:Amino Acid Sequence; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D014961:X-Ray Diffraction
chemical_list: C437968:PLAAT4 protein, human; D012330:RNA, Double-Stranded; D018168:Receptors, Retinoic Acid; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1