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

Brisse, Morgan; Ly, Hinh

LGP2 orthologs are also only found in vertebrates while the next closest related family of proteins (Dicer) are more ancient proteins. It has therefore been proposed that the RIG-I helicase-DExD/H complex may have been duplicated from MDA5 in the common ancestor of vertebrates (184) . The association of the two CARD domains appears to have followed, as individual CARD domains are found in a variety of vertebrates that also encode caspases (344, 345) , but only RIG-I, MDA5, and certain members of the Nacht family of NTPases (346) have two CARD domains. Phylogenetic analysis has shown that the helicase-DExD/H and CARD2 have strong co-evolution history (347, 348) , while CARD1 has evolved more independently (184) . CARD2 appears to have been grafted onto the RIG-I helicase-DExD/H complex first, with the CARD2-MDA5 being duplicated from this event. Finally, CARD1 was grafted onto the CARD2-helicase-DExD/H complex in separate events for RIG-I and MDA5 (184) . In mammals, positive selection can be seen in the flexible hinge region connecting the CARD domains to the helicase in RIG-I and MDA5. RIG-I contains an additional site of positive selection within the Hel1 structural motif (N421), while most of the unique positive selection sites for MDA5 are in regions specific to it, including a 29 amino acid insertion in Hel2 (349) .