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Structure paper

TitleMDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 6668, Year 2021
Publish dateNov 18, 2021
AuthorsQin Yu / Alba Herrero Del Valle / Rahul Singh / Yorgo Modis /
PubMed AbstractOur innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. ...Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease.
External linksNat Commun / PubMed:34795277 / PubMed Central
MethodsEM (helical sym.)
Resolution2.8 - 4.3 Å
Structure data

11937

7bkq

EMDB-11937: CryoEM structure of the MDA5-dsRNA filament in complex with ADP with 92-degree helical twist
PDB-7bkq: CryoEM structure of MDA5-dsRNA filament in complex with ADP with 92-degree helical twist
Method: EM (helical sym.) / Resolution: 3.4 Å

12092

7nga

EMDB-12092, PDB-7nga:
CryoEM structure of the MDA5-dsRNA filament in complex with ADP with 88-degree helical twist
Method: EM (helical sym.) / Resolution: 3.9 Å

12213

7bkp

EMDB-12213, PDB-7bkp:
CryoEM structure of disease related M854K MDA5-dsRNA filament in complex with ATP
Method: EM (helical sym.) / Resolution: 2.8 Å

12288

7niq

EMDB-12288: CryoEM structure of disease related M854K MDA5-dsRNA filament in complex with ADP-AlF4(main class)
PDB-7niq: CryoEM structure of disease related M854K MDA5-dsRNA filament in complex with ADP-AlF4(Major class)
Method: EM (helical sym.) / Resolution: 4.26 Å

12294

7nic

EMDB-12294, PDB-7nic:
CryoEM structure of disease related M854K MDA5-dsRNA filament in complex with ADP-AlF4(minor class)
Method: EM (helical sym.) / Resolution: 4.3 Å

Chemicals

ChemComp-ZN:
Unknown entry

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

ChemComp-MG:
Unknown entry

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

ChemComp-ALF:
TETRAFLUOROALUMINATE ION

Source
  • mus musculus (house mouse)
  • pseudomonas virus phi6 (bacteriophage)
  • synthetic construct (others)
KeywordsIMMUNE SYSTEM / PROTEIN-RNA COMPLEX / HELICAL FILAMENT / ATPASE / INNATE IMMUNE RECEPTOR / ANTIVIRAL PROTEIN

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