title: MDA5 assembles into a polar helical filament on dsRNA.
abstract: Melanoma differentiation-associated protein 5 (MDA5) detects viral dsRNA in the cytoplasm. On binding of RNA, MDA5 forms polymers, which trigger assembly of the signaling adaptor mitochondrial antiviral-signaling protein (MAVS) into its active fibril form. The molecular mechanism of MDA5 signaling is not well understood, however. Here we show that MDA5 forms helical filaments on dsRNA and report the 3D structure of the filaments using electron microscopy (EM) and image reconstruction. MDA5 assembles into a polar, single-start helix around the RNA. Fitting of an MDA5 homology model into the structure suggests a key role for the MDA5 C-terminal domain in cooperative filament assembly. Our study supports a signal transduction mechanism in which the helical array of MDA5 within filaments nucleates the assembly of MAVS fibrils. We conclude that MDA5 is a polymerization-dependent signaling platform that uses the amyloid-like self-propagating properties of MAVS to amplify signaling.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Berke
authors.forename: Xiong
authors.initials: X
authors.lastname: Yu
authors.forename: Yorgo
authors.initials: Y
authors.lastname: Modis
authors.forename: Edward H
authors.initials: EH
authors.lastname: Egelman
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D040681:Structural Homology, Protein
chemical_list: D012330:RNA, Double-Stranded; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; C452815:IFIH1 protein, human; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1