Paramyxovirus V Proteins Disrupt the Fold of the RNA Sensor MDA5 to Inhibit Antiviral Signaling

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...

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Published in:	Science (American Association for the Advancement of Science) Vol. 339; no. 6120; pp. 690 - 693
Main Authors:	Motz, Carina, Schuhmann, Kerstin Monika, Kirchhofer, Axel, Moldt, Manuela, Witte, Gregor, Conzelmann, Karl-Klaus, Hopfner, Karl-Peter
Format:	Journal Article
Language:	English
Published:	United States American Association for the Advancement of Science 08-02-2013 The American Association for the Advancement of Science
Subjects:	Adenosine triphosphatases Adenosine Triphosphate - metabolism Adenosines Amino Acid Motifs Amino Acid Sequence Amino acids Animals Antivirals Children Constants Crystal structure Crystallography, X-Ray DEAD Box Protein 58 DEAD-box RNA Helicases - chemistry DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - metabolism Double stranded RNA Genomics HEK293 Cells Humans Hydrolysis Immunity, Innate Immunology Individualized Instruction Inhibition Interferon-Induced Helicase, IFIH1 Literary Devices Mice Models, Molecular Molecular Sequence Data Mutation Parainfluenza virus Parainfluenza Virus 5 - immunology Paramyxovirus Protein Binding Protein Folding Protein Structure, Tertiary Proteins Receptors Receptors, Immunologic Ribonucleic acid RNA RNA, Double-Stranded - metabolism Sensors Signal Transduction Species Sus scrofa Viral Proteins - chemistry Viral Proteins - genetics Viral Proteins - metabolism Viruses
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.1230949