7r3j
Nativ complex of PqsE and RhlR with the synthetic antagonist mBTLNativ complex of PqsE and RhlR 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] 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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