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

Autor: Lässig C; Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.; Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany., Lammens K; Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.; Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany., Gorenflos López JL; Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.; Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany., Michalski S; Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.; Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany., Fettscher O; Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.; Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany., Hopfner KP; Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.; Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.; Center for Integrated Protein Science Munich, Munich, Germany.
Jazyk: angličtina
Zdroj: ELife [Elife] 2018 Jul 26; Vol. 7. Date of Electronic Publication: 2018 Jul 26.
DOI: 10.7554/eLife.38958
Abstrakt: 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 (Lässig 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.
Competing Interests: CL, KL, JG, SM, OF, KH No competing interests declared
(© 2018, Lässig et al.)
Databáze: MEDLINE
Externí odkaz: