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Edited by Thomas J. Silhavy, Princeton University, Princeton, NJ, and approved October 10, 2017 (received for review July 10, 2017)
Significance
Bacterial ABC transporters typically mediate transport of substrates across the cytoplasmic membrane, using either alternating access or toppling-based mechanisms. The noncanonical ABC transporter MacB does not behave in this manner, but instead couples cytoplasmic ATP hydrolysis with periplasmic conformational changes that drive substrates from the periplasm to the extracellular space via the TolC exit duct. Here we describe the mechanotransmission mechanism of MacB in molecular detail by comparing ATP-bound and nucleotide-free structures. We further show that MacB shares its structural architecture with an entire superfamily of ABC transporters responsible for fundamental bacterial processes, including cell division and outer membrane biogenesis, suggesting a common mode of operation, and raise the possibility of targeting such proteins for the development of new antibiotics.
Abstract
MacB is an ABC transporter that collaborates with the MacA adaptor protein and TolC exit duct to drive efflux of antibiotics and enterotoxin STII out of the bacterial cell. Here we present the structure of ATP-bound MacB and reveal precise molecular details of its mechanism. The MacB transmembrane domain lacks a central cavity through which substrates could be passed, but instead conveys conformational changes from one side of the membrane to the other, a process we term mechanotransmission. Comparison of ATP-bound and nucleotide-free states reveals how reversible dimerization of the nucleotide binding domains drives opening and closing of the MacB periplasmic domains via concerted movements of the second transmembrane segment and major coupling helix. We propose that the assembled tripartite pump acts as a molecular bellows to propel substrates through the TolC exit duct, driven by MacB mechanotransmission. Homologs of MacB that do not form tripartite pumps, but share structural features underpinning mechanotransmission, include the LolCDE lipoprotein trafficking complex and FtsEX cell division signaling protein. The MacB architecture serves as the blueprint for understanding the structure and mechanism of an entire ABC transporter superfamily and the many diverse functions it supports.
Footnotes
↵1A.C. and N.P.G. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: vk103{at}cam.ac.uk.
Author contributions: A.C., N.P.G., E.K., and V.K. designed research, performed research, analyzed data, and wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 5LIL, 5LJ6, 5LJ7, 5LJ8, 5LJ9, 5LJA, and 5NAA).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1712153114/-/DCSupplemental.
Published under the PNAS license.
Mechanotransmission mechanism of MacB
Article Classifications
- Biological Sciences
- Microbiology
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