Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDBDonate
RCSB PDBPDBeBMRBAdv. SearchSearch help

9F20

Cryo-EM structure of the I923V MDA5-dsRNA filament with ADP-AlF4 bound and 88-degree helical twist

Summary for 9F20
Entry DOI10.2210/pdb9f20/pdb
Related9F0J 9F1U
EMDB information50111 50136 50137
DescriptorInterferon-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 Keywordsprotein-rna complex, helical filament, atpase, innate immune receptor, immune system
Biological sourceMus musculus (house mouse)
More
Total number of polymer chains3
Total formula weight126854.45
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 citationSingh, 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: 40450684
DOI: 10.1016/j.celrep.2025.115754
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (4.13 Å)
Structure validation

239492

건을2025-07-30부터공개중

PDB statisticsPDBj update infoContact PDBjnumon