9F3P

Cryo-EM structure of the A946T MDA5-dsRNA filament

Summary for 9F3P

• Entry DOI: 10.2210/pdb9f3p/pdb
• Related: 9F0J 9F1U 9F20 9F2L 9F2W
• EMDB information: 50111 50136 50137 50150 50165 50175
• Descriptor: Interferon-induced helicase C domain-containing protein 1, RNA (5'-R(P*GP*UP*CP*AP*AP*GP*CP*CP*GP*AP*GP*GP*AP*GP*A)-3'), RNA (5'-R(P*UP*CP*UP*CP*CP*UP*CP*GP*GP*CP*UP*UP*GP*AP*C)-3'), ... (4 entities in total)
• Functional Keywords: protein-rna complex, helical filament, atpase, innate immune receptor, immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 3
• Total formula weight: 126368.32

Authors

Singh, R.,Herrero del Valle, A.,Modis, Y. (deposition date: 2024-04-25, release date: 2025-02-26, Last modification date: 2025-06-18)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.97 Å)