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Structural basis for the toxicity of Legionella pneumophila effector SidH

Author

Listed:
  • Rahul Sharma

    (European Molecular Biology Laboratory, 71 avenue des Martyrs)

  • Michael Adams

    (European Molecular Biology Laboratory, 71 avenue des Martyrs)

  • Simonne Griffith-Jones

    (European Molecular Biology Laboratory, 71 avenue des Martyrs)

  • Tobias Sahr

    (Institut Pasteur, Université Paris Cité, Biologie des Bactéries Intracellulaires and CNRS UMR 6047)

  • Laura Gomez-Valero

    (Institut Pasteur, Université Paris Cité, Biologie des Bactéries Intracellulaires and CNRS UMR 6047)

  • Felix Weis

    (European Molecular Biology Laboratory)

  • Michael Hons

    (European Molecular Biology Laboratory, 71 avenue des Martyrs)

  • Sarah Gharbi

    (European Molecular Biology Laboratory, 71 avenue des Martyrs)

  • Rayene Berkane

    (Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital
    Goethe University Frankfurt)

  • Alexandra Stolz

    (Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital
    Goethe University Frankfurt)

  • Carmen Buchrieser

    (Institut Pasteur, Université Paris Cité, Biologie des Bactéries Intracellulaires and CNRS UMR 6047)

  • Sagar Bhogaraju

    (European Molecular Biology Laboratory, 71 avenue des Martyrs)

Abstract

Legionella pneumophila (LP) secretes more than 300 effectors into the host cytosol to facilitate intracellular replication. One of these effectors, SidH, 253 kDa in size with no sequence similarity to proteins of known function is toxic when overexpressed in host cells. SidH is regulated by the LP metaeffector LubX which targets SidH for degradation in a temporal manner during LP infection. The mechanism underlying the toxicity of SidH and its role in LP infection are unknown. Here, we determined the cryo-EM structure of SidH at 2.7 Å revealing a unique alpha helical arrangement with no overall similarity to known protein structures. Surprisingly, purified SidH came bound to a E. coli EF-Tu/t-RNA/GTP ternary complex which could be modeled into the cryo-EM density. Mutation of residues disrupting the SidH-tRNA interface and SidH-EF-Tu interface abolish the toxicity of overexpressed SidH in human cells, a phenotype confirmed in infection of Acanthamoeba castellani. We also present the cryo-EM structure of SidH in complex with a U-box domain containing ubiquitin ligase LubX delineating the mechanism of regulation of SidH. Our data provide the basis for the toxicity of SidH and into its regulation by the metaeffector LubX.

Suggested Citation

  • Rahul Sharma & Michael Adams & Simonne Griffith-Jones & Tobias Sahr & Laura Gomez-Valero & Felix Weis & Michael Hons & Sarah Gharbi & Rayene Berkane & Alexandra Stolz & Carmen Buchrieser & Sagar Bhoga, 2023. "Structural basis for the toxicity of Legionella pneumophila effector SidH," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42683-8
    DOI: 10.1038/s41467-023-42683-8
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Tobias Sahr & Pedro Escoll & Christophe Rusniok & Sheryl Bui & Gérard Pehau-Arnaudet & Gregory Lavieu & Carmen Buchrieser, 2022. "Translocated Legionella pneumophila small RNAs mimic eukaryotic microRNAs targeting the host immune response," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Hyunmin Kim & Tomoko Kubori & Kohei Yamazaki & Mi-Jeong Kwak & Suk-Youl Park & Hiroki Nagai & Joseph P. Vogel & Byung-Ha Oh, 2020. "Structural basis for effector protein recognition by the Dot/Icm Type IVB coupling protein complex," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. Michael Adams & Rahul Sharma & Thomas Colby & Felix Weis & Ivan Matic & Sagar Bhogaraju, 2021. "Structural basis for protein glutamylation by the Legionella pseudokinase SidJ," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    5. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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