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

• Published in: Nature communications 2023-09, Vol.14 (1), p.5696-12, Article 5696
• Main Authors: Custódio, Tânia F., Killer, Maxime, Yu, Dingquan, Puente, Virginia, Teufel, Daniel P., Pautsch, Alexander, Schnapp, Gisela, Grundl, Marc, Kosinski, Jan, Löw, Christian
• Format: Article
• Language: English
• Subjects: 101/1; 101/28; 13/109; 631/45/611; 631/535/1258/1259; 631/535/1267; 631/57/2283; 82/16; 82/80; 82/83; Adapters; Adaptor proteins; Autoimmune diseases; Chronic conditions; Drug development; Histidine; Humanities and Social Sciences; Immune response; Immune system; Innate immunity; Interferon; multidisciplinary; Pathogenesis; Peptides; Proteins; Residues; Science; Science (multidisciplinary); Signal transduction; Systemic lupus erythematosus; Toll-like receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41420-5

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. The peptide/histidine transporter 1, PHT1 (SLC15A4), is required for TLR-IRF5 activation via the adaptor protein TASL. Here, the authors determined the structure of PHT1 in the outward-open conformation and present a model of the PHT1-TASL complex where the first 16 residues of TASL bind into the central cavity of PHT1.