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Structural basis for forming the prion‐like MAVS filament on the mitochondrial membrane (599.1)
Author(s) -
Jiang QiuXing,
Xu Hui,
Zheng Hui,
Huang Lily,
He Xiaojing,
Zhang Xuewu,
Chen Zhijian
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.599.1
Subject(s) - protein filament , microbiology and biotechnology , biophysics , innate immune system , transmembrane protein , transmembrane domain , structural biology , biology , mechanism (biology) , chemistry , membrane , physics , immune system , biochemistry , genetics , receptor , quantum mechanics
Mitochondrial anti‐viral signaling (MAVS) protein is a critical adaptor 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 of MAVS and a truncated MAVS lacking its C‐terminal transmembrane domain. Both structures display a left‐handed three‐stranded helical filament, revealing specific interfaces between individual subunits that are dictated by electrostatic interactions between neighboring strands and conserved 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 the spatial features of 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. Grant Funding Source : NIH, Welch Foundation, AHA and HHMI