1. Immunology and Inflammation
  2. Structural Biology and Molecular Biophysics

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

  1. Charlotte Lässig
  2. Katja Lammens
  3. Jacob Lucián Gorenflos López
  4. Sebastian Michalski
  5. Olga Fettscher
  6. Karl-Peter Hopfner  Is a corresponding author
  1. Ludwig-Maximilians-Universität München, Germany
https://doi.org/10.7554/eLife.38958
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  1. Charlotte Lässig
  2. Katja Lammens
  3. Jacob Lucián Gorenflos López
  4. Sebastian Michalski
  5. Olga Fettscher
  6. Karl-Peter Hopfner
(2018)
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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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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Charlotte Lässig

    Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. Katja Lammens

    Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.

  3. Jacob Lucián Gorenflos López

    Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Sebastian Michalski

    Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.

  5. Olga Fettscher

    Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Karl-Peter Hopfner

    Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
    For correspondence
    hopfner@genzentrum.lmu.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4528-8357

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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  1. Charlotte Lässig
  2. Katja Lammens
  3. Jacob Lucián Gorenflos López
  4. Sebastian Michalski
  5. Olga Fettscher
  6. Karl-Peter Hopfner
(2018)
Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants
eLife 7:e38958.
https://doi.org/10.7554/eLife.38958

Share this article

https://doi.org/10.7554/eLife.38958

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    ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

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