title: Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling.
abstract: The retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) melanoma differentiation-associated protein 5 (MDA5) senses cytoplasmic viral RNA and activates antiviral innate immunity. To reveal how paramyxoviruses counteract this response, we determined the crystal structure of the MDA5 adenosine 5'-triphosphate (ATP)-hydrolysis domain in complex with the viral inhibitor V protein. The V protein unfolded the ATP-hydrolysis domain of MDA5 via a β-hairpin motif and recognized a structural motif of MDA5 that is normally buried in the conserved helicase fold. This leads to disruption of the MDA5 ATP-hydrolysis site and prevention of RNA-bound MDA5 filament formation. The structure explains why V proteins inactivate MDA5, but not RIG-I, and mutating only two amino acids in RIG-I induces robust V protein binding. Our results suggest an inhibition mechanism of RLR signalosome formation by unfolding of receptor and inhibitor.
authors: Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors: Carina
authors: C
authors: Motz
authors: Kerstin Monika
authors: KM
authors: Schuhmann
authors: Axel
authors: A
authors: Kirchhofer
authors: Manuela
authors: M
authors: Moldt
authors: Gregor
authors: G
authors: Witte
authors: Karl-Klaus
authors: KK
authors: Conzelmann
authors: Karl-Peter
authors: KP
authors: Hopfner
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D045402:Parainfluenza Virus 5 / Q000276:immunology; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D034421:Sus scrofa; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; C502891:V protein, Paramyxovirus; D014764:Viral Proteins; D000255:Adenosine Triphosphate; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1