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Upon binding to double-stranded (ds) RNA, MDA5 forms a filamentous assembly along the length of dsRNA and utilizes molecular signatures to discriminate self, versus non-self on the basis of dsRNA length and methylation. Its missense variant rs35667974 is protective for type 1 diabetes, psoriasis, and psoriatic arthritis, but is also found to be associated with an increased risk for ankylosing spondylitis, Crohn\u2019s disease, and ulcerative colitis. To gain insight into the complex role of this variant we performed a structural analysis of MDA5 in complex with dsRNA using molecular dynamics simulations. Our data suggest that while the Ile923Val mutation of the rs35667974 variant does not affect binding to native dsRNA significantly, it displays a destabilizing effect in the presence of 2\u2032-O uridine methylation. Thus, the presence of 2\u2032-O-methylation at the dsRNA introduces a sensing signature that leads to selective reduction of the overall MDA catalytic activity. This study represents an evaluation of the role of the shared rs35667974 variant of autoimmune locus IFIH1, reported to lead to selectively reduced catalytic activity of the modified MDA5 phenotype and, as a consequence, reduced negative feedback on cytokine and chemokine signaling and selectively protection against autoimmunity.<\/jats:p>","DOI":"10.1007\/s00239-022-10090-0","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T08:03:58Z","timestamp":1674029038000},"page":"204-213","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Is the Association of the Rare rs35667974 IFIH1 Gene Polymorphism With Autoimmune Diseases a Case of RNA Epigenetics?"],"prefix":"10.1007","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4683-8071","authenticated-orcid":false,"given":"Athena","family":"Andreou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3931-6232","authenticated-orcid":false,"given":"Athanasios","family":"Papakyriakou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-3452","authenticated-orcid":false,"given":"Maria I.","family":"Zervou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George N.","family":"Goulielmos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0919-0571","authenticated-orcid":false,"given":"Elias E.","family":"Eliopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"10090_CR1","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1021\/ct600329w","volume":"3","author":"R Aduri","year":"2007","unstructured":"Aduri R, Psciuk BT, Saro P et al (2007) AMBER force field parameters for the naturally occurring modified nucleosides in RNA. 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