The RIG-I-like Receptor LGP2 Recognizes the Termini of Double-stranded RNA

• DOI: 10.1074/jbc.m900818200
• Publication Date: 2009-03-12T01:34:25Z
• Authors: Xiaojun Li; C.T. Ranjith-Kumar; Monica T. Brooks; S. Dharmaiah; Andrew B. Herr; Cheng Kao; Pingwei Li
• Keywords: 0301 basic medicine; 0303 health sciences; Interferon-Induced Helicase, IFIH1; Receptors, Retinoic Acid; Crystallography, X-Ray; Protein Structure, Tertiary; 3. Good health; DEAD-box RNA Helicases; Structure-Activity Relationship; 03 medical and health sciences; Mutation; Humans; RNA Helicases; Protein Binding; RNA, Double-Stranded; Signal Transduction

The RIG-I-like receptors (RLRs), RIG-I and MDA5, recognize single-stranded RNA with 5' triphosphates and double-stranded RNA (dsRNA) to initiate innate antiviral immune responses. LGP2, a homolog of RIG-I and MDA5 that lacks signaling capability, regulates the signaling of the RLRs. To establish the structural basis of dsRNA recognition by the RLRs, we have determined the 2.0-A resolution crystal structure of human LGP2 C-terminal domain bound to an 8-bp dsRNA. Two LGP2 C-terminal domain molecules bind to the termini of dsRNA with minimal contacts between the protein molecules. Gel filtration chromatography and analytical ultracentrifugation demonstrated that LGP2 binds blunt-ended dsRNA of different lengths, forming complexes with 2:1 stoichiometry. dsRNA with protruding termini bind LGP2 and RIG-I weakly and do not stimulate the activation of RIG-I efficiently in cells. Surprisingly, full-length LGP2 containing mutations that abolish dsRNA binding retained the ability to inhibit RIG-I signaling.