Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5 Academic Article uri icon


  • 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.

author list (cited authors)

  • Li, X., Lu, C., Stewart, M., Xu, H., Strong, R. K., Igumenova, T., & Li, P.

citation count

  • 78

complete list of authors

  • Li, Xiaojun||Lu, Cheng||Stewart, Mikaela||Xu, Hengyu||Strong, Roland K||Igumenova, Tatyana||Li, Pingwei

publication date

  • June 2009