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

• Published in: The Journal of biological chemistry Vol. 284; no. 20; pp. 13881 - 13891
• Main Authors: Li, Xiaojun, Ranjith-Kumar, C.T., Brooks, Monica T., Dharmaiah, S., Herr, Andrew B., Kao, Cheng, Li, Pingwei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Crystallography, X-Ray; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Humans; Interferon-Induced Helicase, IFIH1; Mutation; Protein Binding - physiology; Protein Structure and Folding; Protein Structure, Tertiary - physiology; Receptors, Retinoic Acid - chemistry; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; RNA Helicases - chemistry; RNA Helicases - genetics; RNA Helicases - metabolism; RNA, Double-Stranded - chemistry; RNA, Double-Stranded - genetics; RNA, Double-Stranded - metabolism; Signal Transduction - physiology; Structure-Activity Relationship
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M900818200

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-Å 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.