The C-terminal regulatory domain is the RNA 5'-triphosphate sensor of RIG-I

Mol Cell. 2008 Feb 1;29(2):169-79. doi: 10.1016/j.molcel.2007.10.032.

Abstract

The ATPase RIG-I senses viral RNAs that contain 5'-triphosphates in the cytoplasm. It initiates a signaling cascade that activates innate immune response by interferon and cytokine production, providing essential antiviral protection for the host. The mode of RNA 5'-triphosphate sensing by RIG-I remains elusive. We show that the C-terminal regulatory domain RD of RIG-I binds viral RNA in a 5'-triphosphate-dependent manner and activates the RIG-I ATPase by RNA-dependent dimerization. The crystal structure of RD reveals a zinc-binding domain that is structurally related to GDP/GTP exchange factors of Rab-like GTPases. The zinc coordination site is essential for RIG-I signaling and is also conserved in MDA5 and LGP2, suggesting related RD domains in all three enzymes. Structure-guided mutagenesis identifies a positively charged groove as likely 5'-triphosphate-binding site of RIG-I. This groove is distinct in MDA5 and LGP2, raising the possibility that RD confers ligand specificity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / immunology
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Binding Sites / genetics
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology
  • DEAD-box RNA Helicases / metabolism*
  • Dimerization
  • Humans
  • Immunity, Innate / physiology
  • Interferon-Induced Helicase, IFIH1
  • Interferons / genetics
  • Interferons / immunology
  • Interferons / metabolism
  • Polyphosphates / chemistry
  • Polyphosphates / immunology
  • Polyphosphates / metabolism*
  • Protein Structure, Tertiary / genetics
  • RNA Caps / chemistry
  • RNA Caps / genetics
  • RNA Caps / immunology
  • RNA Caps / metabolism*
  • RNA Helicases / chemistry
  • RNA Helicases / genetics
  • RNA Helicases / immunology
  • RNA Helicases / metabolism
  • RNA, Viral / chemistry
  • RNA, Viral / genetics
  • RNA, Viral / immunology
  • RNA, Viral / metabolism*
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Substrate Specificity / genetics
  • Zinc / chemistry
  • Zinc / immunology
  • Zinc / metabolism
  • rab GTP-Binding Proteins / chemistry
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / immunology
  • rab GTP-Binding Proteins / metabolism

Substances

  • Polyphosphates
  • RNA Caps
  • RNA, Viral
  • Interferons
  • DHX58 protein, human
  • Adenosine Triphosphatases
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • RNA Helicases
  • rab GTP-Binding Proteins
  • Zinc
  • triphosphoric acid

Associated data

  • PDB/2QFB
  • PDB/2QFD