Parts, assembly and operation of the RIG-I family of motors

•RLRs consist of a DExD/H-box core with appended domains for dsRNA recognition.•RIG-I recognizes triphosphorylated RNA termini while MDA5 binds duplexes internally.•RNA binding partially orders the protein, and stimulates ATP binding/hydrolysis.•ATP binding fully compacts the helicase core and helps eject the signaling domains.•RLRs bind MAVS to effect signaling, although the precise mechanism remains unclear. Host cell invasion is monitored by a series of pattern recognition receptors (PRRs) that activate the innate immune machinery upon detection of a cognate pathogen associated molecular pattern (PAMP). The RIG-I like receptor (RLR) family of PRRs includes three proteins—RIG-I, MDA5, and LGP2—responsible for the detection of intracellular pathogenic RNA. All RLR proteins are built around an ATPase core homologous to those found in canonical Superfamily 2 (SF2) RNA helicases, which has been modified through the addition of novel accessory domains to recognize duplex RNA. This review focuses on the structural bases for pathogen-specific dsRNA binding and ATPase activation in RLRs, differential RNA recognition by RLR family members, and implications for other duplex RNA activated ATPases, such as Dicer.