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Cryo-EM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis

DOI: 10.1016/j.molcel.2018.10.012 DOI Help

Authors: Qin Yu (MRC Laboratory of Molecular Biology) , Kun Qu (MRC Laboratory of Molecular Biology) , Yorgo Modis (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 17434

Open Access Open Access

Abstract: Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Long cytosolic dsRNA is recognized by MDA5. The cooperative assembly of MDA5 into helical filaments on dsRNA nucleates the assembly of a multiprotein type I interferon signaling platform. Here, we determined cryoelectron microscopy (cryo-EM) structures of MDA5-dsRNA filaments with different helical twists and bound nucleotide analogs at resolutions sufficient to build and refine atomic models. The structures identify the filament-forming interfaces, which encode the dsRNA binding cooperativity and length specificity of MDA5. The predominantly hydrophobic interface contacts confer flexibility, reflected in the variable helical twist within filaments. Mutation of filament-forming residues can result in loss or gain of signaling activity. Each MDA5 molecule spans 14 or 15 RNA base pairs, depending on the twist. Variations in twist also correlate with variations in the occupancy and type of nucleotide in the active site, providing insights on how ATP hydrolysis contributes to MDA5-dsRNA recognition.

Keywords: RIG-I-like receptor; RLR; nucleic acid sensing; innate immune pattern recognition; DExD/H-box RNA helicase; superfamily 2 helicases; SF2 helicases; cryoelectron microscopy; cryo-EM; helical reconstruction; ATPase; Aicardi-Goutières syndrome; AGS

Subject Areas: Biology and Bio-materials

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