Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants

Laessig, Charlotte; Lammens, Katja; Lopez, Jacob Lucian Gorenflos; Michalski, Sebastian; Fettscher, Olga und Hopfner, Karl-Peter (2018): Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants. In: eLife, Vol. 7, e38958

Abstract

The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (Lassig et al., 2015), 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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 2050-084X
• Language: English