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

Tânia F. Custódio, Maxime Killer, Dingquan Yu, Virginia Puente, Daniel P. Teufel, Alexander Pautsch, Gisela Schnapp, Marc Grundl, Jan Kosinski and Christian Löw ()
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Tânia F. Custódio: Centre for Structural Systems Biology (CSSB)
Maxime Killer: Centre for Structural Systems Biology (CSSB)
Dingquan Yu: Centre for Structural Systems Biology (CSSB)
Virginia Puente: Centre for Structural Systems Biology (CSSB)
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)
Christian Löw: Centre for Structural Systems Biology (CSSB)

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41420-5

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