A structure-based model of RIG-I activation. (A) In the auto-inhibited state, the CARDs are bound to Hel-2i and thus unavailable for signaling. The CTD, tethered to the red bridging helix by a flexible linker and thus available to sense RNA PAMPs, is shown bound to blunt-ended 5′ ppp-bpRNA. (B) The CTD-bound 5′ppp-bpRNA is pre-oriented to form a network of interactions with the helicase domains Hel-1 and Hel-2i, but not Hel-2, leading to displacement of the CARDs bound to Hel-2i. The CARDs now become potentially available for downstream interactions. In the absence of ATP, this state, visualized by Luo et al. (2011), could revert to the auto-inhibited state (A). (C) ATP binding to its pocket formed at the interface of Hel-1 and Hel-2 tightens and stabilizes the closed form of the structure. Jiang et al. (2011) visualized an “almost closed” version of this state with bound ADP:BeF3 in which the ATP binding motif VI is not engaged. Kowalinski et al. (2011) used the transition-state analog ADP:AlF3 and observed a fully closed form with all ATP-binding motifs configured as required for ATP hydrolysis (Fig. 4B). (D) The RNA and ADP bound state, following ATP hydrolysis and phosphate release, has very recently been visualized by Luo et al. (2012) and is in the semi-open conformation similar to the nucleotide free state (B). Upon ADP release, this state most likely reverts to B. (E) In the case in which the nucleotide bearing the 5′ppp is not base-paired (e.g., arenavirus genomes), the RNA helix is not constrained by its interaction with the CTD and is no longer pre-oriented to form a network of interactions with the helicase domains, and is thus inactive.
