Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

MDA5 and LGP2: Accomplices and Antagonists of Antiviral Signal Transduction.
K. R. Rodriguez, A. M. Bruns, and C. M. Horvath (2014)
J. Virol. 88, 8194-8200
   Abstract »    Full Text »    PDF »
Paramyxovirus V Protein Interaction with the Antiviral Sensor LGP2 Disrupts MDA5 Signaling Enhancement but Is Not Relevant to LGP2-Mediated RLR Signaling Inhibition.
K. R. Rodriguez and C. M. Horvath (2014)
J. Virol. 88, 8180-8188
   Abstract »    Full Text »    PDF »
Immunogenicity of Novel Mumps Vaccine Candidates Generated by Genetic Modification.
P. Xu, Z. Chen, S. Phan, A. Pickar, B. He, and D. S. Lyles (2014)
J. Virol. 88, 2600-2610
   Abstract »    Full Text »    PDF »
Flavivirus NS1 Structures Reveal Surfaces for Associations with Membranes and the Immune System.
D. L. Akey, W. C. Brown, S. Dutta, J. Konwerski, J. Jose, T. J. Jurkiw, J. DelProposto, C. M. Ogata, G. Skiniotis, R. J. Kuhn, et al. (2014)
Science 343, 881-885
   Abstract »    Full Text »    PDF »
Middle East Respiratory Syndrome Coronavirus Accessory Protein 4a Is a Type I Interferon Antagonist.
D. Niemeyer, T. Zillinger, D. Muth, F. Zielecki, G. Horvath, T. Suliman, W. Barchet, F. Weber, C. Drosten, and M. A. Muller (2013)
J. Virol. 87, 12489-12495
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882