MDA5 assembles into a polar helical filament on dsRNA

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 45; pp. 18437 - 18441
• Main Authors: Berke, Ian C., Yu, Xiong, Modis, Yorgo, Egelman, Edward H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.11.2012; National Acad Sciences
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Animals; Antivirals; Biological Sciences; Cytoplasm; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - metabolism; DEAD-box RNA Helicases - ultrastructure; Double stranded RNA; Electron microscopy; Enzymes; HEK293 Cells; Humans; Image Processing, Computer-Assisted; Image reconstruction; Interferon-Induced Helicase, IFIH1; Melanoma; Mice; Microscopy; Models, Molecular; Molecular structure; Molecules; Polymers; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Receptors; Ribonucleic acid; RNA; RNA, Double-Stranded - metabolism; RNA, Double-Stranded - ultrastructure; Sensors; Signal Transduction; Solar fibrils; Structural Homology, Protein
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1212186109

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, singlestart 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.