Journal Article

Structural basis of specific lysine transport by Pseudomonas aeruginosa permease LysP

Bicer, Deniz, Matsuoka, Rei, Sukumar, Preethi, Cheruvara, Harish, Pardon, Els, Steyaert, Jan, Quigley, Andrew, Henderson, Peter J. F., Griese, Julia J., Nji, Emmanuel, Drew, David, Suades, Albert, Moumbock, Aurélien F. A., Caffrey, Martin

2025

Overview

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. Pseudomonas aeruginosa survives extreme acidity by importing lysine through the LysP transporter to regulate acid-resistance genes. Here, authors reveal the cryo-EM structure of LysP and show how specific hydrogen bonds enable lysine recognition.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/326/41/2533 / 631/326/41/2536 / 631/45/535/1258/1259 / 631/45/612/1237 / 631/57/2283 / Acid resistance / Acidity / Antibiotics / Bacteria / Bacterial infections / Bacterial Proteins - chemistry / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Bacterial Proteins - ultrastructure / Biological Transport / Cadaverine / Carboxy-Lyases / Conformation / Cryoelectron Microscopy / Drug development / Homeostasis / Humanities and Social Sciences / Hydrogen bonding / Hydrogen bonds / Hydrogen-Ion Concentration / Hydrophobicity / Lysine / Lysine - chemistry / Lysine - metabolism / Lysine decarboxylase / Models, Molecular / Mortality / multidisciplinary / Nanobodies / Permease / Protein Conformation / Proteolipids - metabolism / Protons / Pseudomonas aeruginosa / Pseudomonas aeruginosa - enzymology / Pseudomonas aeruginosa - genetics / Pseudomonas aeruginosa - metabolism / Recognition / Science / Science (multidisciplinary)