Structural and functional insights into pattern recognition by the innate immune receptor RIG-I

By Yanli Wang, J. Ludwig, Christine Schuberth, Marion Goldeck, M. Schlee, Haitao Li, S. Juranek, G. Sheng, R. Micura, Thomas Tuschl and 2 more. 2010

194 citations recorded by the source corpus.

RIG-I is a cytosolic helicase that senses 5′-ppp RNA contained in negative-strand RNA viruses and triggers innate antiviral immune responses. Calorimetric binding studies established that the RIG-I C-terminal regulatory domain (CTD) binds to blunt-end double-stranded 5′-ppp RNA a factor of 17 more tightly than to its single-stranded counterpart. Here we report on the crystal structure of RIG-I CTD bound to both blunt ends of a self-complementary 5′-ppp dsRNA 12-mer, with interactions involving 5′-pp clearly visible in the complex. The structure, supported by mutation studies, defines how a lysine-rich basic cleft within the RIG-I CTD sequesters the observable 5′-pp of the bound RNA, with a stacked phenylalanine capping the terminal base pair. Key intermolecular interactions observed in the crystalline state are retained in the complex of 5′-ppp dsRNA 24-mer and full-length RIG-I under in vivo conditions, as evaluated from the impact of binding pocket RIG-I mutations and 2′-OCH3 RNA modifications on the interferon response.

Subfields: Immunology, Oncology

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In Immunology

Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, neutral): “Given that the CTD is the primary contributor to RIG-I-RNA binding affinity (Vela et al., 2012; Wang et al., 2010), the loss of interactions between the CTD and the blunt dsRNA terminus and the reduction in Hel2i-RNA interactions is expected to dramatically weaken RIG-I binding to internal RNA…”
Structural Basis of RNA Recognition and Activation by Innate Immune Receptor RIG-I (2011, unknown): “The RD–RNA contacts in the helicase-RD structure are identical to those identified in the structures of the isolated RD bound to dsRN”
Signaling in innate immunity and inflammation. (2012, background): “The extent of IRF3 phosphorylation and dimerization has not been determined in cells lacking TRADD, RIP1, or FADD; it remains possible that these proteins, like TRAF6, contribute to type I Ifn gene expression by activating NF-kB (Wang et al. 2010a).”
A structure-based model of RIG-I activation. (2012, background): “Finally, in a short space of time in 2011, four groups independently reported high-resolution structures of RIG-I and RIG-I RNA complexes that extend previous structural studies that revealed how the CTD preferentially bound 59pppbpRNA (Lu et al. 2010; Wang et al. 2010).”
ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA (2015, background): “Since RD is also required for the displacement of the 2CARD module from SF2, we additionally analyzed a point mutation in RD. K888 mediates triphosphate binding in RD and mutations in this residue inactivate recognition of viral RNA (Cui et al., 2008; Wang et al., 2010).”
RIG-I uses an ATPase-powered translocation-throttling mechanism for kinetic proofreading of RNAs and oligomerization (2018, background): “However, a key mechanism for limiting non-specific RNA binding is a structurally encoded autoinhibition mechanism (Jiang et al., 2011; Kowalinski et al., 2011; Lu et al., 2011; Luo et al., 2011; Wang et al., 2010).”