7r3e
Fusion construct of PqsE and RhlR in complex with the synthetic antagonist mBTL
Structural highlights
FunctionPQSE_PSEAE Required for the biosynthesis of the quorum-sensing signaling molecules 2-heptyl-4(1H)-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal or PQS), which are important for biofilm formation and virulence. Catalyzes the hydrolysis of the intermediate 2-aminobenzoylacetyl-CoA (2-ABA-CoA) to form 2-aminobenzoylacetate (2-ABA), the precursor of HHQ. In vitro, can also hydrolyze other substrates such as S-ethyl-acetothioacetate and acetoacetyl-CoA, but is inactive against anthraniloyl-CoA, malonyl-CoA and octanoyl-CoA (PubMed:25960261, PubMed:27082157). Beyond its thioesterase function, is involved in the regulation of diverse genes coding for key virulence determinants and biofilm development (PubMed:27851827).[1] [2] [3] RHLR_PSEAE Quorum-sensing regulator that controls the expression of multiple virulence factors in response to extracellular signaling molecules called autoinducers (PubMed:7494482, PubMed:8522523, PubMed:15576196). Involved, among others, in the transcriptional regulation of genes that are responsible for rhamnolipid surfactant biosynthesis (PubMed:8144472, PubMed:7604006, PubMed:14526008). Acts by binding to a specific sequence in the rhlAB regulatory region, both in the presence and in the absence of its autoinducer (PubMed:14526008). In the former case it activates transcription of the promoter, whereas in the latter it acts as a transcriptional repressor (PubMed:14526008). Also regulates the expression of the rmlBDAC operon, encoding dTDP-L-rhamnose biosynthetic enzymes, by binding to the rml box in the promoter region (PubMed:22262098). In addition, is involved in the regulation of the production of elastase (lasB) and pyocyanine (PubMed:8144472, PubMed:7604006, PubMed:8522523).[4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedPseudomonas aeruginosa is a major cause of nosocomial infections and also leads to severe exacerbations in cystic fibrosis or chronic obstructive pulmonary disease. Three intertwined quorum sensing systems control virulence of P. aeruginosa, with the rhl circuit playing the leading role in late and chronic infections. The majority of traits controlled by rhl transcription factor RhlR depend on PqsE, a dispensable thioesterase in Pseudomonas Quinolone Signal (PQS) biosynthesis that interferes with RhlR through an enigmatic mechanism likely involving direct interaction of both proteins. Here we show that PqsE and RhlR form a 2:2 protein complex that, together with RhlR agonist N-butanoyl-L-homoserine lactone (C4-HSL), solubilizes RhlR and thereby renders the otherwise insoluble transcription factor active. We determine crystal structures of the complex and identify residues essential for the interaction. To corroborate the chaperone-like activity of PqsE, we design stability-optimized variants of RhlR that bypass the need for C4-HSL and PqsE in activating PqsE/RhlR-controlled processes of P. aeruginosa. Together, our data provide insight into the unique regulatory role of PqsE and lay groundwork for developing new P. aeruginosa-specific pharmaceuticals. Moonlighting chaperone activity of the enzyme PqsE contributes to RhlR-controlled virulence of Pseudomonas aeruginosa.,Borgert SR, Henke S, Witzgall F, Schmelz S, Zur Lage S, Hotop SK, Stephen S, Lubken D, Kruger J, Gomez NO, van Ham M, Jansch L, Kalesse M, Pich A, Bronstrup M, Haussler S, Blankenfeldt W Nat Commun. 2022 Dec 1;13(1):7402. doi: 10.1038/s41467-022-35030-w. PMID:36456567[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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