Abstract
In Pseudomonas aeruginosa, an important opportunistic pathogen that causes numerous acute and chronic infections, the hybrid two-component system (TCS) regulates the swarming ability and biofilm formation with a multistep phospho-relay, and consists of hybrid-sensor histidine kinase (HK), histidine-containing phospho-transfer protein (Hpt) and response regulator (RR). In this work, two crystal structures of HptB and the receiver domain of HK PA1611 (PA1611REC) of P. aeruginosa have been determined in order to elucidate their interactions for the transfer of the phospho-ryl group. The structure of HptB folds into an elongated four-helix bundle - helices α2, α3, α4 and α5, covered by the short N-terminal helix α1. The imidazole side chain of the conserved active-site histidine residue His57, located near the middle of helix α3, protrudes from the bundle and is exposed to solvent. The structure of PA1611REC possesses a conventional (β/α)5 topology with five-stranded parallel β-sheets folded in the central region, surrounded by five α-helices. The divalent Mg2+ ion is located in the negatively charged active-site cleft and interacts with Asp522, Asp565 and Arg567. The HptB-PA1611REC complex is further modeled to analyze the binding surface and interactions between the two proteins. The model shows a shape complementarity between the convex surface of PA1611REC and the kidney-shaped HptB with fewer residues and a different network involved in interactions compared with other TCS complexes, such as SLN1-R1/YPD1 from Saccharomyces cerevisiae and AHK5RD/AHP1 from Arabidopsis thaliana. These structural results provide a better understanding of the TCS in P. aeruginosa and could potentially lead to the discovery of a new treatment for infection.
Highlights
In aiding the adaptation of cells to environmental changes, two-component regulatory systems (TCS) are widely distributed in prokaryotes, whereas few are identified in lower eukaryotic organisms and plants
The system is composed of a sensor histidine kinase (HK), which is autophosphorylated at a conserved histidine residue of its cytoplasmic transmitter domain after sensing outside signals with the extracellular input domain; and a response regulator
HptB exhibits a low level of overall sequence similarity with other histidine-containing phosphotransfer protein (Hpt) proteins/domains [Fig. 2(a)], but they all share a common structural feature as an elongated four-helix bundle, which is kidney-shaped with up-and-down topology and stabilized by inter-helix hydrophobic contacts and hydrogen-bond linkages in the inter-helical regions
Summary
In aiding the adaptation of cells to environmental changes, two-component regulatory systems (TCS) are widely distributed in prokaryotes, whereas few are identified in lower eukaryotic organisms and plants. The basic mechanism of the TCS signaling transduction is the transfer of a phosphoryl group, which serves as a signaling molecule. The system is composed of a sensor histidine kinase (HK), which is autophosphorylated at a conserved histidine residue of its cytoplasmic transmitter domain after sensing outside signals with the extracellular input domain; and a response regulator. 7, 934–948 research papers (RR), which accepts the phosphoryl group at the conserved aspartate residue of the receiver domain (REC) from HK or a histidine-containing phosphotransfer protein (Hpt) (Stock et al, 1989; 2000). Biofilm formation and the implementation of drug resistance are typically regulated by TCS, which makes TCS an attractive target for research and drug intervention (Anjali et al, 2019)
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