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    Arch Biochem Biophys. 2009 Aug 1;488(1):23-33. Epub 2009 Jun 14.

    Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5.

    Li X, Lu C, Stewart M, Xu H, Strong RK, Igumenova T, Li P.

    Source

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.

    Abstract

    RIG-I, MDA5 and LGP2 are cytosolic pattern recognition receptors detecting single-stranded or double-stranded RNA in virally infected cells. The activation of RIG-I or MDA5 stimulates the secretion of type I interferons that play key roles in antiviral immune responses. The C-terminal domains (CTD) of RIG-I and LGP2 are responsible for RNA binding; however, it is not clear how MDA5 binds RNA. To understand the structural basis of dsRNA recognition by MDA5, we have determined the 1.45A resolution structure of the C-terminal domain of human MDA5. The structure revealed a highly conserved fold similar to the structures of RIG-I and LGP2 CTDs. NMR titration of MDA5 CTD with dsRNA demonstrated that a positively charged surface is involved in dsRNA binding. Mutagenesis and RNA binding studies showed that electrostatic interactions play primary roles in dsRNA recognition by MDA5. Like RIG-I and LGP2, MDA5 CTD preferentially binds dsRNA with blunt ends, but does not associate with dsRNA with either 5' or 3' overhangs. Molecular modeling of MDA5 CTD/dsRNA complex suggests that MDA5 CTD may recognize the first turn of blunt-ended dsRNA in a similar manner as LGP2.

    PMID:
    19531363
    [PubMed - indexed for MEDLINE]

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