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PreprintCited by 19Drug Transport and Resistance MechanismsImmune Response and InflammationReceptor Mechanisms and Signaling

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Molecular basis of TASL recruitment by PHT1

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Custódio, Tânia, Killer, Maxime, Yu, Dingquan, Puente, Virginia, Teufel, Daniel, Pautsch, Alexander, Schnapp, Gisela, Grundl, Marc, Kosinski, Jan, Loew, Christian·2023·Nature Communications
DOI 10.21203/rs.3.rs-2646698/v1PMC PMC10502012

Preprint — published as 10.1038/s41467-023-41420-5 · Paper page

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Abstract

PHT1 is a histidine /oligopeptide transporter with an essential role in Toll-like receptor innate immune response. 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 modelling 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.

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Metadata

Authors
Custódio, T., Killer, M., Yu, D., Puente, V., Teufel, D., Pautsch, A., Schnapp, G., Grundl, M., Kosinski, J., & Loew, C.
Affiliations
  • European Molecular Biology Laboratory (DE)
  • Heidelberg University (DE)
  • Boehringer Ingelheim (Germany) (DE)
  • European Molecular Biology Laboratory
  • European Molecular Biology Laboratory Hamburg
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-03-24
Volume
14
Issue
1
Pages
5696-5696
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-2646698/v1
PMC
PMC10502012
OpenAlex
W4386739366
Cited by
19
References
1
Citations by year
2026: 4 · 2025: 5 · 2024: 8 · 2023: 2
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Desy publication database (The Deutsches Elektronen-Synchrotron) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron)
Funders
  • Deutsche Forschungsgemeinschaft (INST 152/772-1, INST 152/772-1 | 152/774-1 | 152/775-1 | 152/776-1 | 152/777-1 FUGG, 152/777 -1 FUGG, 152/775-1, INST 152/772-1|152/774-1|152/775-1|152/776-1, 152/774-1, 152/776-1)
  • Bundesministerium für Bildung und Forschung (05K18YEA)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
PHT1, Toll-like receptor signaling, type I interferon production, IRF5, systemic lupus erythematosus, transporter conformation, innate immunity, autoimmune disease
MeSH terms
Autoimmune Diseases, Histidine, Humans, Interferon Type I, Lupus Erythematosus, Systemic, Adaptor Proteins, Signal Transducing

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