Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants
- Ludwig-Maximilians-Universität München, Germany
Abstract
The innate immune sensor RIG-I detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signalling 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, localised in the ATP binding P-loop, can signal independently of ATP but still dependent on RNA. The structure in complex with dsRNA reveals that C268F helps induce a similar structural conformation in RIG-I than ATP. Our results uncover an unexpected mechanism how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.
Data availability
Diffraction data have been deposited in PDB under the accession code 6GPG.
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Structural Basis for RNA Recognition and Activation of RIG-IPDB accession no 5E3H.
Article and author information
Author details
Karl-Peter Hopfner
Funding
Bayerisches Staatsministerium für Bildung und Kultus, Wissenschaft und Kunst (BioSysNet)
- Karl-Peter Hopfner
German Excellence Initiative (CIPSM)
- Karl-Peter Hopfner
Deutsche Forschungsgemeinschaft (HO2489/8)
- Karl-Peter Hopfner
Deutsche Forschungsgemeinschaft (CRC1054 project B02)
- Katja Lammens
Deutsche Forschungsgemeinschaft (CRC/TRR 237)
- Karl-Peter Hopfner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Lässig et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants
eLife 7:e38958.
https://doi.org/10.7554/eLife.38958
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