| Structural highlights
Function
[TOLC_ECOLI] Outer membrane channel, which is required for the function of several efflux systems such as AcrAB-TolC, AcrEF-TolC, EmrAB-TolC and MacAB-TolC. These systems are involved in export of antibiotics and other toxic compounds from the cell. TolC is also involved in import of colicin E1 into the cells.[1] [2] [3] [4] [5] [MACB_ECOLI] Part of the tripartite efflux system MacAB-TolC. MacB is a non-canonical ABC transporter that contains transmembrane domains (TMD), which form a pore in the inner membrane, and an ATP-binding domain (NBD), which is responsible for energy generation. When overexpressed, the system confers resistance against macrolides composed of 14- and 15-membered lactones but no or weak resistance against 16-membered ones. In addition, the system could also transport R-LPS or a similar glycolipid.[6] [7] [8] [9] [MACA_ECOLI] Part of the tripartite efflux system MacAB-TolC. MacA stimulates the ATPase activity of MacB by promoting the closed ATP-bound state of MacB, increases the capacity of MacB to bind macrolides such as erythromycin, and provides a physical link between MacB and TolC. When overexpressed, the system confers resistance against macrolides composed of 14- and 15-membered lactones but no or weak resistance against 16-membered ones. In addition, MacA binds tightly rough-core lipopolysaccharide (R-LPS), suggesting that the system could also transport R-LPS or a similar glycolipid.[10] [11] [12] [13] [14]
Publication Abstract from PubMed
The MacA-MacB-TolC assembly of Escherichia coli is a transmembrane machine that spans the cell envelope and actively extrudes substrates, including macrolide antibiotics and polypeptide virulence factors. These transport processes are energized by the ATPase MacB, a member of the ATP-binding cassette (ABC) superfamily. We present an electron cryo-microscopy structure of the ABC-type tripartite assembly at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges between a TolC trimer in the outer membrane and a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA is proposed to act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism.
Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump.,Fitzpatrick AWP, Llabres S, Neuberger A, Blaza JN, Bai XC, Okada U, Murakami S, van Veen HW, Zachariae U, Scheres SHW, Luisi BF, Du D Nat Microbiol. 2017 May 15;2:17070. doi: 10.1038/nmicrobiol.2017.70. PMID:28504659[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Morona R, Manning PA, Reeves P. Identification and characterization of the TolC protein, an outer membrane protein from Escherichia coli. J Bacteriol. 1983 Feb;153(2):693-9. PMID:6337123
- ↑ Kobayashi K, Tsukagoshi N, Aono R. Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element. J Bacteriol. 2001 Apr;183(8):2646-53. PMID:11274125 doi:http://dx.doi.org/10.1128/JB.183.8.2646-2653.2001
- ↑ Touze T, Eswaran J, Bokma E, Koronakis E, Hughes C, Koronakis V. Interactions underlying assembly of the Escherichia coli AcrAB-TolC multidrug efflux system. Mol Microbiol. 2004 Jul;53(2):697-706. PMID:15228545 doi:http://dx.doi.org/10.1111/j.1365-2958.2004.04158.x
- ↑ Lin HT, Bavro VN, Barrera NP, Frankish HM, Velamakanni S, van Veen HW, Robinson CV, Borges-Walmsley MI, Walmsley AR. MacB ABC transporter is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA. J Biol Chem. 2009 Jan 9;284(2):1145-54. doi: 10.1074/jbc.M806964200. Epub 2008, Oct 27. PMID:18955484 doi:http://dx.doi.org/10.1074/jbc.M806964200
- ↑ Zakharov SD, Sharma O, Zhalnina M, Yamashita E, Cramer WA. Pathways of colicin import: utilization of BtuB, OmpF porin and the TolC drug-export protein. Biochem Soc Trans. 2012 Dec 1;40(6):1463-8. doi: 10.1042/BST20120211. PMID:23176499 doi:http://dx.doi.org/10.1042/BST20120211
- ↑ Kobayashi N, Nishino K, Yamaguchi A. Novel macrolide-specific ABC-type efflux transporter in Escherichia coli. J Bacteriol. 2001 Oct;183(19):5639-44. PMID:11544226 doi:http://dx.doi.org/10.1128/JB.183.19.5639-5644.2001
- ↑ Tikhonova EB, Devroy VK, Lau SY, Zgurskaya HI. Reconstitution of the Escherichia coli macrolide transporter: the periplasmic membrane fusion protein MacA stimulates the ATPase activity of MacB. Mol Microbiol. 2007 Feb;63(3):895-910. Epub 2007 Jan 4. PMID:17214741 doi:http://dx.doi.org/10.1111/j.1365-2958.2006.05549.x
- ↑ Lin HT, Bavro VN, Barrera NP, Frankish HM, Velamakanni S, van Veen HW, Robinson CV, Borges-Walmsley MI, Walmsley AR. MacB ABC transporter is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA. J Biol Chem. 2009 Jan 9;284(2):1145-54. doi: 10.1074/jbc.M806964200. Epub 2008, Oct 27. PMID:18955484 doi:http://dx.doi.org/10.1074/jbc.M806964200
- ↑ Lu S, Zgurskaya HI. MacA, a periplasmic membrane fusion protein of the macrolide transporter MacAB-TolC, binds lipopolysaccharide core specifically and with high affinity. J Bacteriol. 2013 Nov;195(21):4865-72. doi: 10.1128/JB.00756-13. Epub 2013 Aug, 23. PMID:23974027 doi:http://dx.doi.org/10.1128/JB.00756-13
- ↑ Kobayashi N, Nishino K, Yamaguchi A. Novel macrolide-specific ABC-type efflux transporter in Escherichia coli. J Bacteriol. 2001 Oct;183(19):5639-44. PMID:11544226 doi:http://dx.doi.org/10.1128/JB.183.19.5639-5644.2001
- ↑ Tikhonova EB, Devroy VK, Lau SY, Zgurskaya HI. Reconstitution of the Escherichia coli macrolide transporter: the periplasmic membrane fusion protein MacA stimulates the ATPase activity of MacB. Mol Microbiol. 2007 Feb;63(3):895-910. Epub 2007 Jan 4. PMID:17214741 doi:http://dx.doi.org/10.1111/j.1365-2958.2006.05549.x
- ↑ Lin HT, Bavro VN, Barrera NP, Frankish HM, Velamakanni S, van Veen HW, Robinson CV, Borges-Walmsley MI, Walmsley AR. MacB ABC transporter is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA. J Biol Chem. 2009 Jan 9;284(2):1145-54. doi: 10.1074/jbc.M806964200. Epub 2008, Oct 27. PMID:18955484 doi:http://dx.doi.org/10.1074/jbc.M806964200
- ↑ Modali SD, Zgurskaya HI. The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by MacB transporter. Mol Microbiol. 2011 Aug;81(4):937-51. doi: 10.1111/j.1365-2958.2011.07744.x. Epub, 2011 Jul 4. PMID:21696464 doi:http://dx.doi.org/10.1111/j.1365-2958.2011.07744.x
- ↑ Lu S, Zgurskaya HI. MacA, a periplasmic membrane fusion protein of the macrolide transporter MacAB-TolC, binds lipopolysaccharide core specifically and with high affinity. J Bacteriol. 2013 Nov;195(21):4865-72. doi: 10.1128/JB.00756-13. Epub 2013 Aug, 23. PMID:23974027 doi:http://dx.doi.org/10.1128/JB.00756-13
- ↑ Fitzpatrick AWP, Llabres S, Neuberger A, Blaza JN, Bai XC, Okada U, Murakami S, van Veen HW, Zachariae U, Scheres SHW, Luisi BF, Du D. Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nat Microbiol. 2017 May 15;2:17070. doi: 10.1038/nmicrobiol.2017.70. PMID:28504659 doi:http://dx.doi.org/10.1038/nmicrobiol.2017.70
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