RLR domains and signaling. RLR domains and signaling. Recent structures of domains in RLR signaling are combined here to present the mechanisms involved. Cartoon schematics adjacent to the structures show domain associations and movements in equivalent colors. (A) Structure of RIG-I before RNA binding. RIG-I C-terminal domain (red, PDB ID 4A2X) recognizes 5′-triphosphate RNA (blue and green atoms) to engage with open form (PDB ID 4A2W) of the helicase (yellow, green, cyan) and associated N-terminal CARD domains (violet and blue). (B) RIG-I with pppRNA engaged. RNA association with helicase domains (PDB ID 3TMI) leads to displacement of CARD domains (modeled from PDB ID 4A2W, linker shown as dotted line). (C) Association of CARD domains and ubiquitin binding. Top view of the CARD domain tetramer (PDB ID 4NQK, violet and blue with other 3 copies gray shades) with associated ubiquitin molecules (green). The tetramer has a right-handed helical twist, down going clockwise. (D) Interaction with MAVS CARD domains (PDB ID 4P4H). Side view of the RIG-I CARD domain tetramer (violet, blue) with associated ubiquitin chains (green). Four MAVS CARD domains (yellow/orange) associate with the top surface. (E) Schematic view of signaling. Full-length MAVS is associated with the outer mitochondrial membrane (transmembrane helix in gray) and association with RIG-I cards propagates assembly of MAVS and TRAF signaling. Clare E. Bryant et al. Pharmacol Rev 2015;67:462-504 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics