Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Brisse, Morgan; Ly, Hinh

One of the most obvious distinctions between RIG-I and MDA5 is in the RNA species to which they bind for activation (Figures 1, 5) . RIG-I has the highest affinity for short dsRNA that is tri-phosphorylated at the 5 ′ end (67-75), with RIG-I having been found to directly interact with the 5 ′ tri-phosphate group of the dsRNA (71, 73) . While RIG-I can bind to ss-5 ′ tri-phosphorylated RNA (69), RIG-I cannot be activated by it (69, 168, 169) , likely due to a conformational need to recognize double-stranded RNA. As a result, RIG-I is greatly attenuated by a 5 ′ overhang as well as those with a 3 ′ overhanging the 5 ′ tri-phosphate end (170) . In fact, a single unpaired 5 ′ triphosphorylated nucleotide is sufficient to competitively inhibit RIG-I, which has been exploited by RNA viruses to evade RIG-I recognition and IFN1 signaling (171) . The unique preference of RIG-I for 5 ′ tri-phosphorylated RNA can be explained by the specific orientation that the RIG-I C terminus adopts when directly interacting with the 5 ′ tri-phosphate group of the 5 ′ tri-phosphorylated dsRNA (71, 73) as compared to unphosphorylated blunt-ended dsRNA (172) .