Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I

• Published in: Molecular cell 2014-08, Vol.55 (4), p.511-523
• Main Authors: Wu, Bin, Peisley, Alys, Tetrault, David, Li, Zongli, Egelman, Edward H., Magor, Katharine E., Walz, Thomas, Penczek, Pawel A., Hur, Sun
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Binding Sites - physiology; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - metabolism; Microscopy, Electron; Models, Molecular; Molecular Imprinting - methods; Protein Conformation; Protein Structure, Quaternary; Protein Structure, Tertiary; RNA, Viral - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2014.06.010

RIG-I activates interferon signaling pathways by promoting filament formation of the adaptor molecule, MAVS. Assembly of the MAVS filament is mediated by its CARD domain (CARDMAVS), and requires its interaction with the tandem CARDs of RIG-I (2CARDRIG-I). However, the precise nature of the interaction between 2CARDRIG-I and CARDMAVS, and how this interaction leads to CARDMAVS filament assembly, has been unclear. Here we report a 3.6 Å electron microscopy structure of the CARDMAVS filament and a 3.4 Å crystal structure of the 2CARDRIG-I:CARDMAVS complex, representing 2CARDRIG-I “caught in the act” of nucleating the CARDMAVS filament. These structures, together with functional analyses, show that 2CARDRIG-I acts as a template for the CARDMAVS filament assembly, by forming a helical tetrameric structure and recruiting CARDMAVS along its helical trajectory. Our work thus reveals that signal activation by RIG-I occurs by imprinting its helical assembly architecture on MAVS, a previously uncharacterized mechanism of signal transmission. [Display omitted] •The CARDMAVS filament is a left-handed, single-stranded helix•The CARDMAVS filament shares the same helical symmetry as the 2CARDRIG-I tetramer•The 2CARDRIG-I tetramer serves as a template to nucleate the CARDMAVS filament•CARDMAVS utilizes the same surface to interact with both 2CARDRIG-I and CARDMAVS A viral RNA sensor, RIG-I, activates interferon signaling pathways by promoting filament formation of the adaptor molecule, MAVS. Wu et al. show that RIG-I acts as a template for the CARDMAVS filament assembly by forming a helical tetrameric structure and recruiting individual CARDMAVS along its extended helical trajectory.