Structural basis of specific lysine transport by Pseudomonas aeruginosa permease LysP
Under conditions of extreme acidity, the lysine-specific permease, LysP, not only mediates the import of L-lysine it also interacts with the transcriptional regulator, CadC, to activate expression of the cadAB operon. This operon encodes the lysine decarboxylase, CadA, which converts lysine to cadaverine while consuming a cytoplasmic proton, and the antiporter, CadB, which exports protonated cadaverine in exchange for extracellular lysine. Together, these processes contribute to cytoplasmic pH homeostasis and support bacterial acid resistance - a mechanism essential for the survival of pathogenic bacteria in acidic host environments. Here, we present the cryo-EM structure of LysP from Pseudomonas aeruginosa in an inward-occluded conformation (3.2-5.3 Å resolution), bound to L-lysine and a nanobody. L-Lysine is coordinated by hydrophobic contacts, cation-π interactions, and by hydrogen bonding mostly with polar uncharged residues. Reconstitution of LysP into proteoliposomes confirms specific L-lysine transport, which is competitively inhibited by L-4-thialysine. These findings provide a structural framework for understanding selective lysine recognition and inhibition, with implications for antibacterial drug design.
Authors
- Jan Steyaert (ORCID: https://orcid.org/0000-0002-3825-874X)
- Els Pardon (ORCID: https://orcid.org/0000-0002-2466-0172)
- Preethi Sukumar
- Albert Suades
- Julia J. Griese (ORCID: https://orcid.org/0000-0003-3686-3062)
- Aurélien F. A. Moumbock (ORCID: https://orcid.org/0000-0002-6034-2016)
- Peter J. F. Henderson (ORCID: https://orcid.org/0000-0002-9187-0938)
- David Drew (ORCID: https://orcid.org/0000-0001-8866-6349)
- Harish Cheruvara (ORCID: https://orcid.org/0000-0001-7688-0401)
- Andrew Quigley (ORCID: https://orcid.org/0000-0002-5022-9845)
- Emmanuel Nji (ORCID: https://orcid.org/0000-0001-6991-1046)
- Martin Caffrey (ORCID: https://orcid.org/0000-0002-2931-4551)
- Deniz Bicer
- Rei Matsuoka (ORCID: https://orcid.org/0000-0001-6718-2572)
Institutions
- Uppsala University (SE)
- University of Leeds (GB)
- Vrije Universiteit Brussel (BE)
- University of Freiburg (DE)
- Stockholm University (SE)
- Aarhus University (DK)
- Trinity College Dublin (IE)
- Science for Life Laboratory (SE)
- Kumasi Technical University (GH)
- Diamond Light Source (GB)
- University of Oxford (GB)
- ProterixBio (United States) (US)
- Farm Africa Kenya (KE)
- VIB-VUB Center for Structural Biology (BE)
- National Bioproducts Institute (South Africa) (ZA)
- Centre for Schistosomiasis & Parasitology (CM)
- Institute of Structural and Molecular Biology (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1038/s41467-025-66618-7
- Citations
- 1
- Primary Topic
- Bacterial Genetics and Biotechnology
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Wellcome Trust
- Diamond Light Source
- Wenner-Gren Stiftelserna
- Kempe Foundation
- European Commission
- Science Foundation Ireland
- Fonds Wetenschappelijk Onderzoek
- Vetenskapsrådet
- Umeå Universitet
- Uppsala Universitet
- Kempestiftelserna
- Stockholms Universitet
- Science for Life Laboratory
- Vlaamse regering