Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling

Science. 2013 Feb 8;339(6120):690-3. doi: 10.1126/science.1230949. Epub 2013 Jan 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • HEK293 Cells
  • Humans
  • Hydrolysis
  • Immunity, Innate
  • Interferon-Induced Helicase, IFIH1
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Parainfluenza Virus 5* / immunology
  • Protein Binding
  • Protein Folding
  • Protein Structure, Tertiary
  • RNA, Double-Stranded / metabolism*
  • Signal Transduction
  • Sus scrofa
  • Viral Proteins / chemistry*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • RNA, Double-Stranded
  • V protein, Paramyxovirus
  • Viral Proteins
  • Adenosine Triphosphate
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1

Associated data

  • PDB/4I1S