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Science 339 (6120): 690-693

Copyright © 2013 by the American Association for the Advancement of Science

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

Carina Motz,1 Kerstin Monika Schuhmann,2 Axel Kirchhofer,1,* Manuela Moldt,1 Gregor Witte,1 Karl-Klaus Conzelmann,2 Karl-Peter Hopfner1,3,{dagger}

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.

1 Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
2 Max von Pettenkofer-Institute and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
3 Center for Integrated Protein Sciences, Munich, Germany.

* Present address: Business Consulting, Bayer Business Services GmbH, Leverkusen, Germany.

{dagger}To whom correspondence should be addressed at Gene Center, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. E-mail: hopfner{at}genzentrum.lmu.de


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