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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Crystallography, X-Ray
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DEAD Box Protein 58
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DEAD-box RNA Helicases / chemistry*
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism*
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HEK293 Cells
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Humans
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Hydrolysis
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Immunity, Innate
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Interferon-Induced Helicase, IFIH1
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Mice
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Parainfluenza Virus 5* / immunology
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Protein Binding
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Protein Folding
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Protein Structure, Tertiary
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RNA, Double-Stranded / metabolism*
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Receptors, Immunologic
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Signal Transduction
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Sus scrofa
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Viral Proteins / chemistry*
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Viral Proteins / genetics
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Viral Proteins / metabolism*
Substances
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RNA, Double-Stranded
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Receptors, Immunologic
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V protein, Paramyxovirus
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Viral Proteins
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Adenosine Triphosphate
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RIGI protein, human
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IFIH1 protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1