Figure 4. Model for the impact of Singleton-Merten syndrome mutations on self-RNA-induced RIG-I signaling.

(A) In healthy cells, wild type RIG-I occurs in a signal-off state in which 2CARD is shielded by binding to the insertion domain of SF2. Binding of RIG-I to self-RNAs is efficiently prevented through ATP-turnover-induced dissociation (for a detailed model on self- vs non-self RNA discrimination see also Lässig et al. (2015). (B) RIG-I Singleton-Merten syndrome (SMS) mutations either slow down ATP hydrolysis and stabilize the ATP-state (E373A, left side) or mimic the ATP-bound state (C268F, right side), and thus allow formation of the RIG-I signal-on state. In both cases, loss of ATP hydrolysis enhances the interaction with self-RNA and therefore results in pathogenic signaling. SMS mutations are indicated with a yellow or orange star.