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

Brisse, Morgan; Ly, Hinh

The minimally required and exclusionary features of the 5 ′ and 3 ′ dsRNA ends for RIG-I activation have proven to be complex. Certain studies suggest that a 5 ′ diphosphate group is the minimum feature required for RIG-I binding and activation, with 5 ′ monophosphate dsRNA failing to productively activate RIG-I as compared to 5 ′ di and tri-phosphate dsRNA (173) . Frontiers in Immunology | www.frontiersin.org Additionally, RIG-I poorly distinguishes between dsRNAs with either 5 ′ tri-phosphate and 5 ′ diphosphate group. When the free energies of each interaction are calculated, the affinity for 5 ′ triphosphate being lowered by disassociation of magnesium from the RIG-I/dsRNA complex. Both are significantly more favorable for binding RIG-I monophosphate dsRNA (174) . This similarity in affinity appears to be important in the context of infection with viruses that produce 5 ′ diphosphate RNAs, such as reoviruses (173) . Likewise, the difference of energic binding between monophosphate dsRNA and bi-and triphosphate dsRNAs is likely important for distinction between self (host) and non-self (foreign) RNA, the mechanisms of which will be discussed in detail below. The ATP hydrolysis functions of RIG-I have been shown to drive rapid disassociation from certain RNA features, such as 5 ′ monophosphate dsRNA (174, 175) and 5 ′ OH RNA (144, 176) , which is particularly important for 5 ′ monophosphate dsRNA because it is found in mRNA after decapping during the mRNA degradation process (177) .