title: The RIG-I ATPase domain structure reveals insights into ATP-dependent antiviral signalling.
abstract: RIG-I detects cytosolic viral dsRNA with 5' triphosphates (5'-ppp-dsRNA), thereby initiating an antiviral innate immune response. Here we report the crystal structure of superfamily 2 (SF2) ATPase domain of RIG-I in complex with a nucleotide analogue. RIG-I SF2 comprises two RecA-like domains 1A and 2A and a helical insertion domain 2B, which together form a 'C'-shaped structure. Domains 1A and 2A are maintained in a 'signal-off' state with an inactive ATP hydrolysis site by an intriguing helical arm. By mutational analysis, we show surface motifs that are critical for dsRNA-stimulated ATPase activity, indicating that dsRNA induces a structural movement that brings domains 1A and 2A/B together to form an active ATPase site. The structure also indicates that the regulatory domain is close to the end of the helical arm, where it is well positioned to recruit 5'-ppp-dsRNA to the SF2 domain. Overall, our results indicate that the activation of RIG-I occurs through an RNA- and ATP-driven structural switch in the SF2 domain.
authors: Department of Biochemistry at the Gene Center, Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 25, Munich 81377, Germany.
authors: Filiz
authors: F
authors: Civril
authors: Matthew
authors: M
authors: Bennett
authors: Manuela
authors: M
authors: Moldt
authors: Tobias
authors: T
authors: Deimling
authors: Gregor
authors: G
authors: Witte
authors: Stefan
authors: S
authors: Schiesser
authors: Thomas
authors: T
authors: Carell
authors: Karl-Peter
authors: KP
authors: Hopfner
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D017124:Conserved Sequence / Q000235:genetics; D018360:Crystallography, X-Ray; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011971:Receptors, Immunologic; D012996:Solutions; D000266:Adenylyl Imidodiphosphate; D012313:RNA; D000255:Adenosine Triphosphate; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases