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Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (&lt;xref ref-type=\"bibr\" rid=\"bib19\"&gt;L\u00e4ssig et al., 2015&lt;\/xref&gt;), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.<\/jats:p>","DOI":"10.7554\/elife.38958","type":"journal-article","created":{"date-parts":[[2018,7,26]],"date-time":"2018-07-26T08:00:15Z","timestamp":1532592015000},"source":"Crossref","is-referenced-by-count":37,"title":["Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6253-7880","authenticated-orcid":true,"given":"Charlotte","family":"L\u00e4ssig","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"},{"name":"Gene Center, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, 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