Structural insights into RNA recognition by RIG-I

By D. Luo, S. Ding, Adriana Vela, Andrew S. Kohlway, B. Lindenbach, Anna Marie Pyle. 2011

404 citations recorded by the source corpus.

Summary Intracellular RIG-I-like receptors (RLRs, including RIG-I, MDA-5, and LGP-2) recognize viral RNAs as pathogen-associated molecular patterns (PAMPs) and initiate an antiviral immune response. To understand the molecular basis of this process, we determined the crystal structure of RIG-I in complex with double-stranded RNA. The dsRNA is sheathed within a network of protein domains that include a conserved “helicase” domain (regions HEL1 and HEL2), a specialized insertion domain (HEL2i), and a C-terminal regulatory domain (CTD). A V-shaped pincer connects HEL2 and the CTD by gripping an α-helical shaft that extends from HEL1. In this way, the pincer coordinates functions of all the domains and couples RNA binding with ATP hydrolysis. RIG-I falls within the Dicer-RIG-I clade of super family 2 of helicases and this structure reveals complex interplay between motor domains, accessory mechanical domains and RNA that has implications for understanding the nanomechanical function this protein family and other ATPases more broadly.

Subfields: Immunology, Molecular Biology

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Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, neutral): “Shared architectural features of RIG-I complexes with host and viral dsRNA ligands As observed in previous crystallographic studies, all complexes visualized by cryo-EM reveal a familiar ring-like structure in which the domains of RIG-I are wrapped around dsRNA and the blunt duplex terminus is cappe”
Defining the functional determinants for RNA surveillance by RIG-I (2013, positive): “The crystallization and data collection of RIG-I (DCARDs:1–229) binary and ternary complexes were performed as described previously, with modifications [20].”
The RIG-I ATPase core has evolved a functional requirement for allosteric stabilization by the Pincer domain (2014, methodology): “Recombinant RIG-I proteins were expressed and purified as reported previously (12,35).”
Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding (2016, background): “In many of the structures, including the apoform (PDB ID: 4A2W) (10), the RNA bound form (PDB ID: 2YKG, 3ZD6, 4BPB, 5F9F, 5F9H) (9,41,46) and the RNA–ADP bound form (PDB ID: 4AY2) (20), Ser411 interacts directly with Met761 (762 in duck), which is a residue within helix 1 of the Pincer domain.”
Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants (2018, background): “SF2 and RD are crucial for RNA-recognition of RLRs, whereas 2CARD communicates successful RNA-binding events to downstream signaling factors (Jiang et al., 2011; Kowalinski et al., 2011; Luo et al., 2011).”
Cytosolic Sensing of Viruses (2013, background): “Binding at the CTD is communicated N-terminally via a long and flexible elbow-like or V-shaped ‘‘pincer’’ (P) domain (also known as the bridging helices) that connects the Hel1 domain to the CTD (Jiang et al., 2011b; Kowalinski et al., 2011; Luo et al., 2011).”
ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA (2015, background): “…approximately matches the footprint of dsRNA across the two SF2 RecA domains in the crystal structure of ADP BeFx-bound RIG-I (Jiang et al., 2011; Kohlway et al., 2013; Kowalinski et al., 2011; Luo et al., 2011) and also meets the requirements for activation of RIG-I’s ATPase Figure supplement 1.”
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).”
Establishing the role of ATP for the function of the RIG-I innate immune sensor (2015, methodology): “While robust signaling is often associated with ATP hydrolysis activity (Yoneyama et al., 2004; Bamming and Horvath, 2009; Luo et al., 2011; Kohlway et al., 2013; Patel et al., 2013; Peisley et al., 2013; Rawling et al., 2015), the ability of an RNA ligand to stimulate RIG-I ATPase activity does…”
An evolving arsenal: viral RNA detection by RIG-I-like receptors (2014, background): “The CTD is mechanically coupled to the ATPase core and Hel2i via a pincer domain that transduces information on molecular interactions throughout the protein [9,10 ,11 ,12].”
Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5 (2015, neutral): “In accordance with the canonical functions of the various conserved helicase motifs [59] and the footprint spanning 9–10 bp of dsRNA according to crystal structures [30], the SF2 helicase family conserved motifs primarily involved in RNA binding are motifs Ia [29, 30], Ib and Ic [28, 29], IIa [28–30”
Pattern recognition receptors in health and diseases (2021, background): “128 Under bacterial infection of the Indian major carp Labeo rohita, LGP2 gene expression was significantly increased after dsRNA and various PAMPs were stimulated, indicating that LGP2 can act as an antiviral and antibacterial cytoplasmic receptor.129 Although the RLR family members have similar st”