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Structure paper

TitleMolecular basis of autoimmune disease protection by MDA5 variants.
Journal, issue, pagesCell Rep, Vol. 44, Issue 6, Page 115754, Year 2025
Publish dateMay 30, 2025
AuthorsRahul Singh / Joe D Joiner / Alba Herrero Del Valle / Marleen Zwaagstra / Ida Jobe / Brian J Ferguson / Frank J M van Kuppeveld / Yorgo Modis /
PubMed AbstractMDA5 recognizes double-stranded RNA (dsRNA) from viruses and retroelements. Cooperative filament formation and ATP-dependent proofreading confer MDA5 with the necessary sensitivity and specificity ...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.
External linksCell Rep / PubMed:40450684 / PubMed Central
MethodsEM (helical sym.)
Resolution3.35 - 4.21 Å
Structure data

50111

9f0j

EMDB-50111, PDB-9f0j:
Cryo-EM structure of the I923V MDA5-dsRNA filament without nucleotide
Method: EM (helical sym.) / Resolution: 3.35 Å

50136

9f1u

EMDB-50136, PDB-9f1u:
Cryo-EM structure of the I923V MDA5-dsRNA filament with ADP-AlF4 bound and 81-degree helical twist
Method: EM (helical sym.) / Resolution: 3.67 Å

50137

9f20

EMDB-50137, PDB-9f20:
Cryo-EM structure of the I923V MDA5-dsRNA filament with ADP-AlF4 bound and 88-degree helical twist
Method: EM (helical sym.) / Resolution: 4.13 Å

50150

9f2l

EMDB-50150, PDB-9f2l:
Cryo-EM structure of the I923V MDA5-dsRNA filament with ADP-AlF4 bound and 73-degree helical twist
Method: EM (helical sym.) / Resolution: 3.86 Å

50165

9f2w

EMDB-50165, PDB-9f2w:
Cryo-EM structure of the I923V MDA5-dsRNA filament in complex with ATP
Method: EM (helical sym.) / Resolution: 4.21 Å

50175

9f3p

EMDB-50175, PDB-9f3p:
Cryo-EM structure of the A946T MDA5-dsRNA filament
Method: EM (helical sym.) / Resolution: 3.97 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-ALF:
TETRAFLUOROALUMINATE ION

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / PROTEIN-RNA COMPLEX / HELICAL FILAMENT / ATPASE / INNATE IMMUNE RECEPTOR

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