9F20
Cryo-EM structure of the I923V MDA5-dsRNA filament with ADP-AlF4 bound and 88-degree helical twist
Summary for 9F20
Entry DOI | 10.2210/pdb9f20/pdb |
Related | 9F0J 9F1U |
EMDB information | 50111 50136 50137 |
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'), ... (6 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 | 126854.45 |
Authors | Singh, R.,Herrero del Valle, A.,Modis, Y. (deposition date: 2024-04-20, 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 Cited by 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: 40450684DOI: 10.1016/j.celrep.2025.115754 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (4.13 Å) |
Structure validation
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