Cryo-EM Structures of MDA5-dsRNA Filaments at Different Stages of ATP Hydrolysis

Molecular Cell
Qin YuYorgo Modis

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.

Citations

Nov 8, 2019·Protein Science : a Publication of the Protein Society·Cassie M ZerbeJames L Cole
Mar 24, 2020·Nature Reviews. Immunology·Jan Rehwinkel, Michaela U Gack
Jun 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Charles Bou-Nader, Jinwei Zhang
Aug 6, 2019·Frontiers in Immunology·Morgan Brisse, Hinh Ly
Feb 15, 2021·Biological Chemistry·Pascal Donsbach, Dagmar Klostermeier
Nov 19, 2019·Trends in Immunology·Felix Streicher, Nolwenn Jouvenet

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