In other bacterial species, multiple proteins with structural homology to TolC exist, such as in Pseudomonas species, where at least 18 of these TolC-like proteins have been identified as purpose-evolved conduits. coli, this trimeric TolC conduit subunit is then engaged either onto AcrAB or onto one of 8 other distinct efflux pumps. To achieve this structure, the TolC polypeptide needs to be folded into staves, 3 of which are assembled together to form a transmembrane β-barrel embedded in the outer membrane ( Fig 1C) as well as an α-barrel that extends 100 Å into the periplasm. TolC is the archetypal conduit of tripartite efflux pumps and contains a characteristic αβ-barrel architecture ( Fig 1B). IMC, inner membrane channel OEP, outer membrane efflux protein OMF, outer membrane factor PAP, periplasmic adaptor protein PGN, peptidoglycan. Cylinders represent α-helices arrows represent β-strands. The characteristic OEP regions are indicated. (C) Structural map of one TolC monomer (without its signal peptide), based on its crystal structure (PDB: 1EK9) over residues 1–428 and as predicted using PSIPRED 4.0 over residues 429–471. One of the 3 monomers is coloured pink for clarity. Sizes of each structural domain are indicated to the right. The pump comprises an IMC protein from the RND, ABC, or MFS superfamilies, a PAP, and an OMF family component, like TolC. (A) Schematic of an efflux pump removing harmful substances. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This work was supported by a National Health and Medical Research Council ( ) Program Grant (1092262 to T.L.). Received: ApAccepted: DecemPublished: January 21, 2022Ĭopyright: © 2022 Stubenrauch et al. PLoS Biol 20(1):Īcademic Editor: Csaba Pál, Biological Research Centre, HUNGARY The characteristics of this assembly pathway have impact for the acquisition of efflux pumps across bacterial species and for the development of new antimicrobial compounds that inhibit efflux pump function.Ĭitation: Stubenrauch CJ, Bamert RS, Wang J, Lithgow T (2022) A noncanonical chaperone interacts with drug efflux pumps during their assembly into bacterial outer membranes. Using TolC as a model protein, we demonstrate that assembly of conduit subunits into the outer membrane uses the chaperone TAM to physically organise the membrane-embedded staves of the conduit subunit of the efflux pump. Complex phylogenetics support the concept that gene cassettes encoding the subunits for these pumps are commonly acquired by horizontal gene transfer. Here, we map the distribution of efflux pumps across bacterial lineages to show these proteins are more widespread than previously recognised. The overall architecture of these efflux pumps is highly conserved: with an inner membrane energy-transducing subunit coupled via an adaptor protein to an outer membrane conduit subunit that enables toxic compounds to be expelled into the environment. Bacteria have membrane-spanning efflux pumps to secrete toxic compounds ranging from heavy metal ions to organic chemicals, including antibiotic drugs.
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