MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
| Autor: | Qin Yu, Yorgo Modis, Alba Herrero del Valle, Rahul Singh |
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| Přispěvatelé: | Yu, Qin [0000-0001-9265-632X], Herrero Del Valle, Alba [0000-0001-8153-6146], Singh, Rahul [0000-0001-8397-0202], Modis, Yorgo [0000-0002-6084-0429], Apollo - University of Cambridge Repository, Herrero del Valle, Alba [0000-0001-8153-6146] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular 82/29 Interferon-Induced Helicase IFIH1 Protein Conformation ATPase viruses General Physics and Astronomy medicine.disease_cause 631/45/173 631/45/535/1258/1259 Adenosine Triphosphate 0302 clinical medicine ATP hydrolysis Interferon Adenosine Triphosphatases 0303 health sciences Mutation Multidisciplinary biology Chemistry 631/45/500 article food and beverages MDA5 Chronic inflammation 3. Good health Cell biology RNA silencing Enzyme mechanisms RNA Viral Protein Binding medicine.drug Science Allosteric regulation Mutation Missense General Biochemistry Genetics and Molecular Biology 96/95 03 medical and health sciences medicine Humans 82/83 RNA Double-Stranded 030304 developmental biology Inflammation 631/250/262/2106/2518 Cryoelectron Microscopy 101/28 fungi RNA General Chemistry Immunity Innate HEK293 Cells 631/250/256/2515 RIG-I-like receptors biology.protein Nucleic Acid Conformation 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) Nature Communications, 12 (1) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA. |
| Databáze: | OpenAIRE |
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