Journal Article

PHPPUBDB-24959

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Paramyxovirus V Proteins Disrupt the Fold of the RNA Sensor MDA5 to Inhibit Antiviral Signaling

Motz, C. ; Schuhmann, K. M. ; Kirchhofer, A. ; Moldt, M. ; Witte, G. ; Conzelmann, K.-K. ; Hopfner, K.-P. (Corresponding author)Extern* ; DESY

2013

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Please use a persistent id in citations: doi:10.1126/science.1230949

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.

Keyword(s): Adenosine Triphosphate: metabolism (MeSH) ; Amino Acid Motifs (MeSH) ; Amino Acid Sequence (MeSH) ; Animals (MeSH) ; Crystallography, X-Ray (MeSH) ; DEAD-box RNA Helicases: chemistry (MeSH) ; DEAD-box RNA Helicases: genetics (MeSH) ; DEAD-box RNA Helicases: metabolism (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Hydrolysis (MeSH) ; Immunity, Innate (MeSH) ; Mice (MeSH) ; Models, Molecular (MeSH) ; Molecular Sequence Data (MeSH) ; Mutation (MeSH) ; Protein Binding (MeSH) ; Protein Folding (MeSH) ; Protein Structure, Tertiary (MeSH) ; RNA, Double-Stranded: metabolism (MeSH) ; Signal Transduction (MeSH) ; Simian virus 5: immunology (MeSH) ; Sus scrofa (MeSH) ; Viral Proteins: chemistry (MeSH) ; Viral Proteins: genetics (MeSH) ; Viral Proteins: metabolism (MeSH) ; RNA, Double-Stranded ; V protein, Paramyxovirus ; Viral Proteins ; Adenosine Triphosphate ; DDX58 protein, human ; DEAD-box RNA Helicases ; IFIH1 protein, human

Note: Post referee fulltext in progress; Embargo 6 months from publication

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Contributing Institute(s):

1. Experiments with synchrotron radiation (HASYLAB(-2012))
2. EMBL (EMBL(-2012))

Research Program(s):

1. DORIS Beamline D1.2 (POF2-54G13) (POF2-54G13)

Experiment(s):

1. DORIS Beamline D1.2 (DORIS III)

Appears in the scientific report 2013

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Database coverage:
; No Author Disambiguation

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