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Structural and functional insights into the periplasmic detector domain of the GacS histidine kinase controlling biofilm formation in Pseudomonas aeruginosa

Abstract : Pseudomonas aeruginosa is an opportunistic pathogenic bacterium responsible for both acute and chronic infections and has developed resistance mechanisms due to its ability to promote biofilm formation and evade host adaptive immune responses. Here, we investigate the functional role of the periplasmic detector domain (GacS PD) from the membrane-bound GacS histidine kinase, which is one of the key players for biofilm formation and coordination of bacterial lifestyles. A gacS mutant devoid of the periplasmic detector domain is severely defective in biofilm formation. Functional assays indicate that this effect is accompanied by concomitant changes in the expression of the two RsmY/Z small RNAs that control activation of GacA-regulated genes. The solution NMR structure of GacS PD reveals a distinct PDC/PAS α/β fold characterized by a three-stranded β-sheet flanked by α-helices and an atypical major loop. Point mutations in a putative ligand binding pocket lined by positively-charged residues originating primarily from the major loop impaired biofilm formation. These results demonstrate the functional role of GacS PD , evidence critical residues involved in GacS/GacA signal transduction system that regulates biofilm formation, and document the evolutionary diversity of the PDC/PAS domain fold in bacteria. To cope with environmental changes and develop colonization strategies, bacteria have evolved several sensing systems, including cell-surface signaling systems, quorum sensing, cyclic di-GMP, and the predominant two-component signal-transduction systems (TCS). By modulating cellular functions in response to environmental changes, TCSs play essential roles for the adaptation and survival of organisms 1, 2. Typically, a TCS comprises a membrane-embedded histidine kinase sensor (HK), which acts mainly as a dimeric assembly, and a cognate response regulator (RR). Detection of an environmental stimuli by the HK detector domain triggers autophosphorylation of the HK cytoplasmic domain 3, 4 , leading to activation of a phosphorelay mechanism ending onto the cognate RR to mediate expression of various target genes 5. P. aeruginosa is a major opportunistic pathogen, responsible for nosocomial infections causing severe infections in vulnerable patients such as those with cystic fibrosis or hospitalized with cancer, severe burns and in intensive care units. P. aeruginosa is able to switch from a planktonic (free swimming) to a sessile (biofilm) lifestyle and several TCSs play a critical role in controlling this switch 6, 7. In the free-swimming state responsible for acute infection, bacteria can cross host barriers and proliferate inside the host using motility and virulence factors that are secreted in the extracellular space or directly injected into the host cells using the type III secretion systems 8. Chronic infection is characterized by formation of an antibiotic-resistant biofilm in which intricate bacterial communities are embedded within a matrix of exopolysaccharides and DNA 9. In this particular state, bacteria concomitantly secrete toxins delivered by the type VI secretion system (H1-T6SS), which are used to kill and compete with other species in a crowded and enclosed community 10–13 .
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Ahmad Ali-Ahmad, Firas Fadel, Corinne Sebban-Kreuzer, Moly Ba, Gauthier Dangla Pélissier, et al.. Structural and functional insights into the periplasmic detector domain of the GacS histidine kinase controlling biofilm formation in Pseudomonas aeruginosa. Scientific Reports, Nature Publishing Group, 2017, 7 (1), ⟨10.1038/s41598-017-11361-3⟩. ⟨hal-01770068⟩



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