title: Structural basis for the prion-like MAVS filaments in antiviral innate immunity.
abstract: Mitochondrial antiviral signaling (MAVS) protein is required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling cascades, but the underlying structural mechanism is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N-terminal caspase activation and recruitment domain (CARD) of MAVS and a truncated MAVS lacking part of the proline-rich region and the C-terminal transmembrane domain. Both structures are left-handed three-stranded helical filaments, revealing specific interfaces between individual CARD subunits that are dictated by electrostatic interactions between neighboring strands and hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments. DOI: http://dx.doi.org/10.7554/eLife.01489.001.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Xiaojing
authors.initials: X
authors.lastname: He
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Lily J
authors.initials: LJ
authors.lastname: Huang
authors.forename: Fajian
authors.initials: F
authors.lastname: Hou
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Yu
authors.forename: Michael Jason
authors.initials: MJ
authors.lastname: de la Cruz
authors.forename: Brian
authors.initials: B
authors.lastname: Borkowski
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Qiu-Xing
authors.initials: QX
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000595:Amino Acid Sequence; D020285:Cryoelectron Microscopy; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007113:Immunity, Innate; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D017354:Point Mutation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D029082:Sendai virus / Q000276:immunology*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C512612:MAVS protein, mouse; C505371:MAVS protein, human
keywords: MAVS; cryoEM reconstruction; innate immunity; prion-like filaments; three-stranded filaments