The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA

Nucleic Acids Res. 2009 Apr;37(6):2014-25. doi: 10.1093/nar/gkp059. Epub 2009 Feb 10.

Abstract

RIG-I and MDA5 sense cytoplasmic viral RNA and set-off a signal transduction cascade, leading to antiviral innate immune response. The third RIG-I-like receptor, LGP2, differentially regulates RIG-I- and MDA5-dependent RNA sensing in an unknown manner. All three receptors possess a C-terminal regulatory domain (RD), which in the case of RIG-I senses the viral pattern 5'-triphosphate RNA and activates ATP-dependent signaling by RIG-I. Here we report the 2.6 A crystal structure of LGP2 RD along with in vitro and in vivo functional analyses and a homology model of MDA5 RD. Although LGP2 RD is structurally related to RIG-I RD, we find it rather binds double-stranded RNA (dsRNA) and this binding is independent of 5'-triphosphates. We identify conserved and receptor-specific parts of the RNA binding site. Latter are required for specific dsRNA binding by LGP2 RD and could confer pattern selectivity between RIG-I-like receptors. Our data furthermore suggest that LGP2 RD modulates RIG-I-dependent signaling via competition for dsRNA, another pattern sensed by RIG-I, while a fully functional LGP2 is required to augment MDA5-dependent signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / metabolism
  • Humans
  • Interferon-Induced Helicase, IFIH1
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Polyphosphates / chemistry
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA Helicases / chemistry*
  • RNA Helicases / genetics
  • RNA Helicases / metabolism
  • RNA, Double-Stranded / chemistry*
  • RNA, Double-Stranded / metabolism
  • RNA-Binding Proteins / chemistry*
  • Scattering, Small Angle
  • Signal Transduction
  • X-Ray Diffraction

Substances

  • Polyphosphates
  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • DHX58 protein, human
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • RNA Helicases
  • triphosphoric acid