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PMID:18243112

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Citation

Cui, S, Eisenächer, K, Kirchhofer, A, Brzózka, K, Lammens, A, Lammens, K, Fujita, T, Conzelmann, KK, Krug, A and Hopfner, KP (2008) The C-terminal regulatory domain is the RNA 5'-triphosphate sensor of RIG-I. Mol. Cell 29:169-79

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.

Links

PubMed Online version:10.1016/j.molcel.2007.10.032

Keywords

Adenosine Triphosphatases/chemistry; Adenosine Triphosphatases/genetics; Adenosine Triphosphatases/immunology; Adenosine Triphosphatases/metabolism; Animals; Binding Sites/genetics; Cell Line; 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; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DDX58

enables

GO:0008270: zinc ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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