9F2W

Cryo-EM structure of the I923V MDA5-dsRNA filament in complex with ATP

9F2W の概要

• エントリーDOI: 10.2210/pdb9f2w/pdb
• 関連するPDBエントリー: 9F0J 9F1U 9F20 9F2L
• EMDBエントリー: 50111 50136 50137 50150 50165
• 分子名称: Interferon-induced helicase C domain-containing protein 1, RNA (5'-R(P*CP*AP*AP*GP*CP*CP*GP*AP*GP*GP*AP*GP*AP*U)-3'), RNA (5'-R(P*AP*UP*CP*UP*CP*CP*UP*CP*GP*GP*CP*UP*UP*G)-3'), ... (5 entities in total)
• 機能のキーワード: protein-rna complex, helical filament, atpase, innate immune receptor, immune system
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 126181.07

構造登録者

Singh, R.,Herrero del Valle, A.,Modis, Y. (登録日: 2024-04-24, 公開日: 2025-02-26, 最終更新日: 2025-06-18)

主引用文献

Singh, R.,Joiner, J.D.,Herrero Del Valle, A.,Zwaagstra, M.,Jobe, I.,Ferguson, B.J.,van Kuppeveld, F.J.M.,Modis, Y.
Molecular basis of autoimmune disease protection by MDA5 variants.
Cell Rep, 44:115754-115754, 2025

PubMed Abstract: MDA5 recognizes double-stranded RNA (dsRNA) from viruses and retroelements. Cooperative filament formation and ATP-dependent proofreading confer MDA5 with the necessary sensitivity and specificity for dsRNA. Many MDA5 genetic variants are associated with protection from autoimmune disease while increasing the risk of infection and chronic inflammation. How these variants affect RNA sensing remains unclear. Here, we determine the consequences of autoimmune-protective variants on the molecular structure and activities of MDA5. Rare variants E627 and I923V reduce the interferon response to picornavirus infection. E627 does not bind RNA. I923V is ATPase hyperactive, causing premature dissociation from dsRNA. Cryoelectron microscopy (cryo-EM) structures of MDA5 I923V bound to dsRNA at different stages of ATP hydrolysis reveal smaller RNA binding interfaces, leading to excessive proofreading activity. Variants R843H and T946A, which are genetically linked and cause mild phenotypes, did not affect cytokine induction, suggesting an indirect disease mechanism. In conclusion, autoimmune-protective MDA5 variants dampen MDA5-dependent signaling via multiple mechanisms.

PubMed: 40450684
DOI: 10.1016/j.celrep.2025.115754

実験手法

ELECTRON MICROSCOPY (4.21 Å)