期刊
SCIENCE
卷 339, 期 6120, 页码 690-693出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1230949
关键词
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资金
- German Research Council [Deutsche Forschungsgemeinschaft (DFG)] [GRK1721]
- NIH [U19AI083025]
- Bavarian government (BioSysNet)
- Excellence Initiative of the German Ministry of Education and Science (Center for Integrated Proteins Science)
- DFG [GRK1202]
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 beta-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.
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