%0 Journal Article
%A Motz, C.
%A Schuhmann, K. M.
%A Kirchhofer, A.
%A Moldt, M.
%A Witte, G.
%A Conzelmann, K.-K.
%A Hopfner, K.-P.
%A DESY
%T Paramyxovirus V Proteins Disrupt the Fold of the RNA Sensor MDA5 to Inhibit Antiviral Signaling
%J Science
%V 339
%@ 0036-8075
%M PHPPUBDB-24959
%P 693
%D 2013
%Z Post referee fulltext in progress; Embargo 6 months from publication 
%X 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.
%K Adenosine Triphosphate: metabolism
%K Amino Acid Motifs
%K Amino Acid Sequence
%K Animals
%K Crystallography, X-Ray
%K DEAD-box RNA Helicases: chemistry
%K DEAD-box RNA Helicases: genetics
%K DEAD-box RNA Helicases: metabolism
%K HEK293 Cells
%K Humans
%K Hydrolysis
%K Immunity, Innate
%K Mice
%K Models, Molecular
%K Molecular Sequence Data
%K Mutation
%K Protein Binding
%K Protein Folding
%K Protein Structure, Tertiary
%K RNA, Double-Stranded: metabolism
%K Signal Transduction
%K Simian virus 5: immunology
%K Sus scrofa
%K Viral Proteins: chemistry
%K Viral Proteins: genetics
%K Viral Proteins: metabolism
%K RNA, Double-Stranded (NLM Chemicals)
%K V protein, Paramyxovirus (NLM Chemicals)
%K Viral Proteins (NLM Chemicals)
%K Adenosine Triphosphate (NLM Chemicals)
%K DDX58 protein, human (NLM Chemicals)
%K DEAD-box RNA Helicases (NLM Chemicals)
%K IFIH1 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:23328395
%U <Go to ISI:>//WOS:000314585600041
%R 10.1126/science.1230949
%U https://bib-pubdb1.desy.de/record/141093