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• W2076375475 startingPage "805" @default.
• W2076375475 abstract "Secondary active transporters undergo large conformational changes to facilitate the efflux of substrates across the lipid bilayer. Among the smallest known transport proteins are members of the small multidrug resistance (SMR) family that are composed of four transmembrane (TM) domains and assemble into dimers. An unanswered question in the SMR field is how the dimerization domain (TM4) is coupled with the substrate-binding chamber (TM1–3). To provide insight for this essential aspect of ion-coupled transport, we carried out a structure-function study on the SMR protein EmrE using solid-state NMR spectroscopy in lipid bilayers and resistance assays in Escherichia coli. The chemical shifts for EmrE were consistent with β-strand secondary structure for the loop connecting TM3 and TM4. Based on these structural results, EmrE mutants were created to ascertain whether a specific loop length and composition were necessary for function. A linker encompassing six extra Gly residues relative to wild-type EmrE failed to give resistance; however, the number of residues in the loop was not the only criterion for a functional efflux pump. Replacement of the central hydrophobic residue with Gly (L83G) also conferred no ethidium resistance phenotype, which supported the conclusion that the structure and length of the loop were both essential for ion-coupled transport. Taken together with a bioinformatics analysis, a structured linker is likely conserved across the SMR family to play an active role in mediating the conformational switch between inward-open and outward-open states necessary for drug efflux. These findings underscore the important role loops can play in mediating efflux.EmrE is a multidrug transporter.ResultsNMR spectroscopy was used to reveal a structured loop adjoining the substrate-binding and dimerization domains.ConclusionThe linker structure and composition are conserved across the small multidrug resistance family and necessary for ion-coupled transport.SignificanceLoops in secondary active transporters can play an active role in efflux pump function and require characterization in lipid bilayers. Secondary active transporters undergo large conformational changes to facilitate the efflux of substrates across the lipid bilayer. Among the smallest known transport proteins are members of the small multidrug resistance (SMR) family that are composed of four transmembrane (TM) domains and assemble into dimers. An unanswered question in the SMR field is how the dimerization domain (TM4) is coupled with the substrate-binding chamber (TM1–3). To provide insight for this essential aspect of ion-coupled transport, we carried out a structure-function study on the SMR protein EmrE using solid-state NMR spectroscopy in lipid bilayers and resistance assays in Escherichia coli. The chemical shifts for EmrE were consistent with β-strand secondary structure for the loop connecting TM3 and TM4. Based on these structural results, EmrE mutants were created to ascertain whether a specific loop length and composition were necessary for function. A linker encompassing six extra Gly residues relative to wild-type EmrE failed to give resistance; however, the number of residues in the loop was not the only criterion for a functional efflux pump. Replacement of the central hydrophobic residue with Gly (L83G) also conferred no ethidium resistance phenotype, which supported the conclusion that the structure and length of the loop were both essential for ion-coupled transport. Taken together with a bioinformatics analysis, a structured linker is likely conserved across the SMR family to play an active role in mediating the conformational switch between inward-open and outward-open states necessary for drug efflux. These findings underscore the important role loops can play in mediating efflux.EmrE is a multidrug transporter. NMR spectroscopy was used to reveal a structured loop adjoining the substrate-binding and dimerization domains. The linker structure and composition are conserved across the small multidrug resistance family and necessary for ion-coupled transport." @default.
• W2076375475 created "2016-06-24" @default.
• W2076375475 creator A5000085857 @default.
• W2076375475 creator A5033631103 @default.
• W2076375475 creator A5044049726 @default.
• W2076375475 creator A5085478746 @default.
• W2076375475 date "2015-01-01" @default.
• W2076375475 modified "2023-10-16" @default.
• W2076375475 title "A Structured Loop Modulates Coupling between the Substrate-binding and Dimerization Domains in the Multidrug Resistance Transporter EmrE" @default.
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• W2076375475 doi "https://doi.org/10.1074/jbc.m114.601963" @default.
• W2076375475 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4294503" @default.
• W2076375475 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25406320" @default.
• W2076375475 hasPublicationYear "2015" @default.
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