Structural insights intoPseudomonas aeruginosalysine-specific uptake mechanism for extremely low pH regulation

Abstract

AbstractUnder conditions of extremely low pH, in addition to transporting lysine, bacterial lysine-specific permease (LysP) interacts with the transcriptional regulator CadC to upregulatecadBAoperon expression.cadBAencodes CadA, which decarboxylates lysine to cadaverine, and CadB, which exports cadaverine to the environment to reduce acidity. This process is crucial for survival of pathogenic bacteria in their hosts. Here, we report the inward-occluded (3.2 – 5.3 Å) cryo-EM structure ofPseudomonas aeruginosaLysP bound to L-lysine and in complex with a nanobody. L-lysine is coordinated by hydrophobic stacking, cation-π interactions and hydrogen bonding mostly with polar uncharged LysP residues. LysP reconstituted into liposomes showed robust and specific transport of L-lysine with the transport being inhibited by L-4-thialysine (S-2-aminoethyl-L-cysteine). These findings inform our understanding of the specific recognition, inhibition, and transport mechanism of L-lysine by LysP, which will have important ramifications for the design of antibiotics to target bacterial LysP.