title: Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG-I.
abstract: 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 (CARD(MAVS)), and requires its interaction with the tandem CARDs of RIG-I (2CARD(RIG-I)). However, the precise nature of the interaction between 2CARD(RIG-I) and CARD(MAVS), and how this interaction leads to CARD(MAVS) filament assembly, has been unclear. Here we report a 3.6 Å electron microscopy structure of the CARD(MAVS) filament and a 3.4 Å crystal structure of the 2CARD(RIG-I):CARD(MAVS) complex, representing 2CARD(RIG-I) "caught in the act" of nucleating the CARD(MAVS) filament. These structures, together with functional analyses, show that 2CARD(RIG-I) acts as a template for the CARD(MAVS) filament assembly, by forming a helical tetrameric structure and recruiting CARD(MAVS) 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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Alys
authors.initials: A
authors.lastname: Peisley
authors.affiliation: Department of Biological Sciences and the Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E9, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Tetrault
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Zongli
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Egelman
authors.affiliation: Department of Biological Sciences and the Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E9, Canada.
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Magor
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
authors.forename: Pawel A
authors.initials: PA
authors.lastname: Penczek
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA. Electronic address: sun.hur@childrens.harvard.edu.
authors.forename: Sun
authors.initials: S
authors.lastname: Hur
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology*; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000378:metabolism; D008854:Microscopy, Electron; D008958:Models, Molecular; D054802:Molecular Imprinting / Q000379:methods*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D012367:RNA, Viral; D053487:DEAD-box RNA Helicases