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Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1

Author

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  • Tânia F. Custódio

    (Centre for Structural Systems Biology (CSSB)
    European Molecular Biology Laboratory (EMBL) Hamburg)

  • Maxime Killer

    (Centre for Structural Systems Biology (CSSB)
    European Molecular Biology Laboratory (EMBL) Hamburg
    Collaboration for joint PhD degree between EMBL, and Heidelberg University, Faculty of Biosciences)

  • Dingquan Yu

    (Centre for Structural Systems Biology (CSSB)
    European Molecular Biology Laboratory (EMBL) Hamburg
    Collaboration for joint PhD degree between EMBL, and Heidelberg University, Faculty of Biosciences)

  • Virginia Puente

    (Centre for Structural Systems Biology (CSSB)
    European Molecular Biology Laboratory (EMBL) Hamburg)

  • Daniel P. Teufel

    (Boehringer Ingelheim Pharma)

  • Alexander Pautsch

    (Boehringer Ingelheim Pharma)

  • Gisela Schnapp

    (Boehringer Ingelheim Pharma)

  • Marc Grundl

    (Boehringer Ingelheim Pharma)

  • Jan Kosinski

    (Centre for Structural Systems Biology (CSSB)
    European Molecular Biology Laboratory (EMBL) Hamburg
    European Molecular Biology Laboratory)

  • Christian Löw

    (Centre for Structural Systems Biology (CSSB)
    European Molecular Biology Laboratory (EMBL) Hamburg)

Abstract

PHT1 is a histidine /oligopeptide transporter with an essential role in Toll-like receptor innate immune responses. It can act as a receptor by recruiting the adaptor protein TASL which leads to type I interferon production via IRF5. Persistent stimulation of this signalling pathway is known to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Understanding how PHT1 recruits TASL at the molecular level, is therefore clinically important for the development of therapeutics against SLE and other autoimmune diseases. Here we present the Cryo-EM structure of PHT1 stabilized in the outward-open conformation. By combining biochemical and structural modeling techniques we propose a model of the PHT1-TASL complex, in which the first 16 N-terminal TASL residues fold into a helical structure that bind in the central cavity of the inward-open conformation of PHT1. This work provides critical insights into the molecular basis of PHT1/TASL mediated type I interferon production.

Suggested Citation

  • Tânia F. Custódio & Maxime Killer & Dingquan Yu & Virginia Puente & Daniel P. Teufel & Alexander Pautsch & Gisela Schnapp & Marc Grundl & Jan Kosinski & Christian Löw, 2023. "Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41420-5
    DOI: 10.1038/s41467-023-41420-5
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