Abstract
ABC (ATP-binding cassette) transporters are ubiquitous integral membrane proteins catalyzing the active export or import of structurally and functionally unrelated compounds. In humans, these proteins are clinically and economically important, as their dysfunction is responsible for a number of diseases. In the case of multidrug resistance (MDR) ABC exporters, they particularly confer resistance to a broad spectrum of toxic compounds, placing them in the focus of clinical research. However, ABC-mediated drug resistance is not only restricted to humans. In yeast for example, MDR is called pleiotropic drug resistance (PDR). Important and well-studied members of the PDR subfamily of ABC transporters are Pdr5 from Saccharomyces cerevisiae and its homolog Cdr1 from Candida albicans. Mutational studies of these two transporters provided many insights into the complexity and conceivable mechanism of the interdomain cross-talk that transmits the energy gained from ATP hydrolysis to the substrate translocation process across the membrane. In this review, we summarize and discuss our current knowledge of the interdomain cross-talk as well as new results obtained for asymmetric ABC transporters and derive possible structural and functional implications for Pdr5.
Acknowledgments
We apologize to all our colleagues whose contribution were not referenced appropriately due to space limitations. Furthermore, we thank Dr. Xia, NIH, for kindly providing the coordinates of the homology model of Pdr5. Our research was supported by grants of the DFG, AiF and the EU to L.S.
References
Al-Shawi, M.K. and Omote, H. (2005). The remarkable transport mechanism of P-glycoprotein: a multidrug transporter. J. Bioenerg. Biomembr. 37, 489–496.10.1007/s10863-005-9497-5Search in Google Scholar
Aller, S.G., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., Harrell, P.M., Trinh, Y.T., Zhang, Q., Urbatsch, I.L. et al. (2009). Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323, 1718–1722.10.1126/science.1168750Search in Google Scholar
Ananthaswamy, N., Rutledge, R., Sauna, Z.E., Ambudkar, S.V., Dine, E., Nelson, E., Xia, D., and Golin, J. (2010). The signaling interface of the yeast multidrug transporter Pdr5 adopts a cis conformation, and there are functional overlap and equivalence of the deviant and canonical Q-loop residues. Biochemistry 49, 4440–4449.10.1021/bi100394jSearch in Google Scholar
Balzi, E., Wang, M., Leterme, S., Van Dyck, L., and Goffeau, A. (1994). PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J. Biol. Chem. 269, 2206–2214.10.1016/S0021-9258(17)42155-7Search in Google Scholar
Bao, H. and Duong, F. (2012). Discovery of an auto-regulation mechanism for the maltose ABC transporter MalFGK2. PLoS One 7, e34836.10.1371/journal.pone.0034836Search in Google Scholar
Biemans-Oldehinkel, E., Doeven, M.K., and Poolman, B. (2006). ABC transporter architecture and regulatory roles of accessory domains. FEBS Lett. 580, 1023–1035.10.1016/j.febslet.2005.11.079Search in Google Scholar
Bissinger, P.H. and Kuchler, K. (1994). Molecular cloning and expression of the Saccharomyces cerevisiae STS1 gene product. A yeast ABC transporter conferring mycotoxin resistance. J. Biol. Chem. 269, 4180–4186.10.1016/S0021-9258(17)41760-1Search in Google Scholar
Davidson, A.L., Shuman, H.A., and Nikaido, H. (1992). Mechanism of maltose transport in Escherichia coli: transmembrane signaling by periplasmic binding proteins. Proc. Natl. Acad. Sci. USA 89, 2360–2364.10.1073/pnas.89.6.2360Search in Google Scholar
Dawson, R.J. and Locher, K.P. (2006). Structure of a bacterial multidrug ABC transporter. Nature 443, 180–185.10.1038/nature05155Search in Google Scholar
Decottignies, A., Kolaczkowski, M., Balzi, E., and Goffeau, A. (1994). Solubilization and characterization of the overexpressed PDR5 multidrug resistance nucleotide triphosphatase of yeast. J. Biol. Chem. 269, 12797–12803.10.1016/S0021-9258(18)99946-1Search in Google Scholar
Dou, W., Zhu, J., Wang, T., Wang, W., Li, H., Chen, X., and Guan, W. (2016). Mutations of charged amino acids at the cytoplasmic end of transmembrane helix 2 affect transport activity of the budding yeast multidrug resistance protein Pdr5p. FEMS Yeast Res. 16, 1567–1364.10.1093/femsyr/fow031Search in Google Scholar
Downes, M.T., Mehla, J., Ananthaswamy, N., Wakschlag, A., Lamonde, M., Dine, E., Ambudkar, S.V., and Golin, J. (2013). The transmission interface of the Saccharomyces cerevisiae multidrug transporter Pdr5: Val-656 located in intracellular loop 2 plays a major role in drug resistance. Antimicrob. Agents Chemother. 57, 1025–1034.10.1128/AAC.02133-12Search in Google Scholar
Eckford, P.D. and Sharom, F.J. (2009). ABC efflux pump-based resistance to chemotherapy drugs. Chem. Rev. 109, 2989–3011.10.1021/cr9000226Search in Google Scholar
Egner, R., Rosenthal, F.E., Kralli, A., Sanglard, D., and Kuchler, K. (1998). Genetic separation of FK506 susceptibility and drug transport in the yeast Pdr5 ATP-binding cassette multidrug resistance transporter. Mol. Biol. Cell 9, 523–543.10.1091/mbc.9.2.523Search in Google Scholar
Ernst, R., Klemm, R., Schmitt, L., and Kuchler, K. (2005). Yeast ATP – binding cassette transporters: cellular cleaning pumps. Methods Enzymol. 400, 460–484.10.1016/S0076-6879(05)00026-1Search in Google Scholar
Ernst, R., Kueppers, P., Klein, C.M., Schwarzmueller, T., Kuchler, K., and Schmitt, L. (2008). A mutation of the H-loop selectively affects rhodamine transport by the yeast multidrug ABC transporter Pdr5. Proc. Natl. Acad. Sci. USA 105, 5069–5074.10.1073/pnas.0800191105Search in Google Scholar PubMed PubMed Central
Ernst, R., Kueppers, P., Stindt, J., Kuchler, K., and Schmitt, L. (2010). Multidrug efflux pumps: substrate selection in ATP-binding cassette multidrug efflux pumps – first come, first served? FEBS J. 277, 540–549.10.1111/j.1742-4658.2009.07485.xSearch in Google Scholar PubMed
Furman, C., Mehla, J., Ananthaswamy, N., Arya, N., Kulesh, B., Kovach, I., Ambudkar, S.V., and Golin, J. (2013). The deviant ATP-binding site of the multidrug efflux pump Pdr5 plays an active role in the transport cycle. J. Biol. Chem. 288, 30420–30431.10.1074/jbc.M113.494682Search in Google Scholar PubMed PubMed Central
Golin, J. and Ambudkar, S.V. (2015). The multidrug transporter Pdr5 on the 25th anniversary of its discovery: an important model for the study of asymmetric ABC transporters. Biochem. J. 467, 353–363.10.1042/BJ20150042Search in Google Scholar PubMed PubMed Central
Golin, J., Barkatt, A., Cronin, S., Eng, G., and May, L. (2000). Chemical specificity of the PDR5 multidrug resistance gene product of Saccharomyces cerevisiae based on studies with tri-n-alkyltin chlorides. Antimicrob. Agents Chemother. 44, 134–138.10.1128/AAC.44.1.134-138.2000Search in Google Scholar PubMed PubMed Central
Golin, J., Ambudkar, S.V., Gottesman, M.M., Habib, A.D., Sczepanski, J., Ziccardi, W., and May, L. (2003). Studies with novel Pdr5p substrates demonstrate a strong size dependence for xenobiotic efflux. J. Biol. Chem. 278, 5963–5969.10.1074/jbc.M210908200Search in Google Scholar PubMed
Golin, J., Kon, Z.N., Wu, C.P., Martello, J., Hanson, L., Supernavage, S., Ambudkar, S.V., and Sauna, Z.E. (2007). Complete inhibition of the Pdr5p multidrug efflux pump ATPase activity by its transport substrate clotrimazole suggests that GTP as well as ATP may be used as an energy source. Biochemistry 46, 13109–13119.10.1021/bi701414fSearch in Google Scholar PubMed
Gottesman, M.M., Fojo, T., and Bates, S.E. (2002). Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48–58.10.1038/nrc706Search in Google Scholar PubMed
Gupta, R.P., Kueppers, P., Schmitt, L., and Ernst, R. (2011). The multidrug transporter Pdr5: a molecular diode? Biol. Chem. 392, 53–60.10.1515/bc.2011.011Search in Google Scholar PubMed
Gupta, R.P., Kueppers, P., Hanekop, N., and Schmitt, L. (2014). Generating symmetry in the asymmetric ATP-binding cassette (ABC) transporter Pdr5 from Saccharomyces cerevisiae. J. Biol. Chem. 289, 15272–15279.10.1074/jbc.M114.553065Search in Google Scholar PubMed PubMed Central
Hirata, D., Yano, K., Miyahara, K., and Miyakawa, T. (1994). Saccharomyces cerevisiae Ydr1, which encodes a member of the ATP-binding cassette (Abc) superfamily, is required for multidrug-resistance. Curr. Gen. 26, 285–294.10.1007/BF00310491Search in Google Scholar PubMed
Hohl, M., Briand, C., Grutter, M.G., and Seeger, M.A. (2012). Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation. Nat. Struct. Mol. Biol. 19, 395–402.10.1038/nsmb.2267Search in Google Scholar PubMed
Hollenstein, K., Dawson, R.J., and Locher, K.P. (2007). Structure and mechanism of ABC transporter proteins. Curr. Opin. Struct. Biol. 17, 412–418.10.1016/j.sbi.2007.07.003Search in Google Scholar PubMed
Hubacek, J.A., Berge, K.E., Cohen, J.C., and Hobbs, H.H. (2001). Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum. Mutat. 18, 359–360.10.1002/humu.1206Search in Google Scholar PubMed
Jardetzky, O. (1966). Simple allosteric model for membrane pumps. Nature 211, 969–970.10.1038/211969a0Search in Google Scholar PubMed
Kim Chiaw, P., Eckford, P.D., and Bear, C.E. (2011). Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy. Essays Biochem. 50, 233–248.10.1042/bse0500233Search in Google Scholar
Krasowska, A., Lukaszewicz, M., Bartosiewicz, D., and Sigler, K. (2010). Cell ATP level of Saccharomyces cerevisiae sensitively responds to culture growth and drug-inflicted variations in membrane integrity and PDR pump activity. Biochem. Biophys. Res. Commun. 395, 51–55.10.1016/j.bbrc.2010.03.133Search in Google Scholar
Kueppers, P., Gupta, R.P., Stindt, J., Smits, S.H., and Schmitt, L. (2013). Functional impact of a single mutation within the transmembrane domain of the multidrug ABC transporter Pdr5. Biochemistry 52, 2184–2195.10.1021/bi3015778Search in Google Scholar
Lamping, E., Baret, P.V., Holmes, A.R., Monk, B.C., Goffeau, A., and Cannon, R.D. (2010). Fungal PDR transporters: phylogeny, topology, motifs and function. Fungal Genet. Biol. 47, 127–142.10.1016/j.fgb.2009.10.007Search in Google Scholar
Lee, J.Y., Kinch, L.N., Borek, D.M., Wang, J., Wang, J., Urbatsch, I.L., Xie, X.S., Grishin, N.V., Cohen, J.C., Otwinowski, Z., et al. (2016). Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533, 561–564.10.1038/nature17666Search in Google Scholar
Leppert, G., McDevitt, R., Falco, S.C., Van Dyk, T.K., Ficke, M.B., and Golin, J. (1990). Cloning by gene amplification of two loci conferring multiple drug resistance in Saccharomyces. Genetics 125, 13–20.10.1093/genetics/125.1.13Search in Google Scholar
Lerner-Marmarosh, N., Gimi, K., Urbatsch, I.L., Gros, P., and Senior, A.E. (1999). Large scale purification of detergent-soluble P-glycoprotein from Pichia pastoris cells and characterization of nucleotide binding properties of wild-type, Walker A, and Walker B mutant proteins. J. Biol. Chem. 274, 34711–34718.10.1074/jbc.274.49.34711Search in Google Scholar
Litman, T., Zeuthen, T., Skovsgaard, T., and Stein, W.D. (1997). Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim. Biophys. Acta 1361, 169–176.10.1016/S0925-4439(97)00027-6Search in Google Scholar
Livnat-Levanon, N., A, I.G., Ben-Tal, N., and Lewinson, O. (2016). The uncoupled ATPase activity of the ABC transporter BtuC2D2 leads to a hysteretic conformational change, conformational memory, and improved activity. Sci. Rep. 6, 21696.10.1038/srep21696Search in Google Scholar PubMed PubMed Central
Mehla, J., Ernst, R., Moore, R., Wakschlag, A., Marquis, M.K., Ambudkar, S.V., and Golin, J. (2014). Evidence for a molecular diode-based mechanism in a multispecific ATP-binding cassette (ABC) exporter: SER-1368 as a gatekeeping residue in the yeast multidrug transporter Pdr5. J. Biol. Chem. 289, 26597–26606.10.1074/jbc.M114.586032Search in Google Scholar PubMed PubMed Central
Oancea, G., O’Mara, M.L., Bennett, W.F., Tieleman, D.P., Abele, R., and Tampe, R. (2009). Structural arrangement of the transmission interface in the antigen ABC transport complex TAP. Proc. Natl. Acad. Sci. USA 106, 5551–5556.10.1073/pnas.0811260106Search in Google Scholar PubMed PubMed Central
Oldham, M.L., Davidson, A.L., and Chen, J. (2008). Structural insights into ABC transporter mechanism. Curr. Opin. Struct. Biol. 18, 726–733.10.1016/j.sbi.2008.09.007Search in Google Scholar PubMed PubMed Central
Oswald, C., Holland, I.B., and Schmitt, L. (2006). The motor domains of ABC-transporters. What can structures tell us? Naunyn-Schmiedeberg’s Arch. Pharmacol. 372, 385–399.Search in Google Scholar
Paumi, C.M., Chuk, M., Snider, J., Stagljar, I., and Michaelis, S. (2009). ABC transporters in Saccharomyces cerevisiae and their interactors: new technology advances the biology of the ABCC (MRP) subfamily. Microbiol. Mol. Biol. Rev. 73, 577–593.10.1128/MMBR.00020-09Search in Google Scholar PubMed PubMed Central
Pfaller, M.A. and Diekema, D.J. (2007). Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20, 133–163.10.1128/CMR.00029-06Search in Google Scholar PubMed PubMed Central
Prasad, R. and Goffeau, A. (2012). Yeast ATP-binding cassette transporters conferring multidrug resistance. Annu. Rev. Microbiol. 66, 39–63.10.1146/annurev-micro-092611-150111Search in Google Scholar PubMed
Procko, E., Ferrin-O’Connell, I., Ng, S.L., and Gaudet, R. (2006). Distinct structural and functional properties of the ATPase sites in an asymmetric ABC transporter. Mol. Cell 24, 51–62.10.1016/j.molcel.2006.07.034Search in Google Scholar PubMed
Puri, N., Prakash, O., Manoharlal, R., Sharma, M., Ghosh, I., and Prasad, R. (2010). Analysis of physico-chemical properties of substrates of ABC and MFS multidrug transporters of pathogenic Candida albicans. Eur. J. Med. Chem. 45, 4813–4826.10.1016/j.ejmech.2010.07.050Search in Google Scholar PubMed
Reich-Slotky, R., Panagiotidis, C., Reyes, M., and Shuman, H.A. (2000). The detergent-soluble maltose transporter is activated by maltose binding protein and Verapamil. J. Bacteriol. 182, 993–1000.10.1128/JB.182.4.993-1000.2000Search in Google Scholar PubMed PubMed Central
Rutledge, R.M., Esser, L., Ma, J., and Xia, D. (2011). Toward understanding the mechanism of action of the yeast multidrug resistance transporter Pdr5p: a molecular modeling study. J. Struct. Biol. 173, 333–344.10.1016/j.jsb.2010.10.012Search in Google Scholar PubMed PubMed Central
Safa, A.R. (2004). Identification and characterization of the binding sites of P-glycoprotein for multidrug resistance-related drugs and modulators. Curr. Med. Chem. Anticancer Agents 4, 1–17.10.2174/1568011043482142Search in Google Scholar PubMed PubMed Central
Sauna, Z.E., Bohn, S.S., Rutledge, R., Dougherty, M.P., Cronin, S., May, L., Xia, D., Ambudkar, S.V., and Golin, J. (2008). Mutations define cross-talk between the N-terminal nucleotide-binding domain and transmembrane helix-2 of the yeast multidrug transporter Pdr5: possible conservation of a signaling interface for coupling ATP hydrolysis to drug transport. J. Biol. Chem. 283, 35010–35022.10.1074/jbc.M806446200Search in Google Scholar PubMed PubMed Central
Seelig, A. (1998). A general pattern for substrate recognition by P-glycoprotein. Eur. J. Biochem. 251, 252–261.10.1046/j.1432-1327.1998.2510252.xSearch in Google Scholar PubMed
Shah, A.H., Rawal, M.K., Dhamgaye, S., Komath, S.S., Saxena, A.K., and Prasad, R. (2015). Mutational analysis of intracellular loops identify cross talk with nucleotide binding domains of yeast ABC transporter Cdr1p. Sci. Rep. 5, 11211.10.1038/srep11211Search in Google Scholar PubMed PubMed Central
Shukla, S., Saini, P., Smriti, Jha, S., Ambudkar, S.V., and Prasad, R. (2003). Functional characterization of Candida albicans ABC transporter Cdr1p. Eukaroyt. Cell 2, 1361–1375.10.1128/EC.2.6.1361-1375.2003Search in Google Scholar PubMed PubMed Central
Shukla, S., Ambudkar, S.V., and Prasad, R. (2004). Substitution of threonine-1351 in the multidrug transporter Cdr1p of Candida albicans results in hypersusceptibility to antifungal agents and threonine-1351 is essential for synergic effects of calcineurin inhibitor FK520. J. Antimicrob. Chemother. 54, 38–45.10.1093/jac/dkh308Search in Google Scholar PubMed
Shukla, S., Rai, V., Banerjee, D., and Prasad, R. (2006). Characterization of Cdr1p, a major multidrug efflux protein of Candida albicans: purified protein is amenable to intrinsic fluorescence analysis. Biochemistry 45, 2425–2435.10.1021/bi0519147Search in Google Scholar PubMed
Turk, D., Hall, M.D., Chu, B.F., Ludwig, J.A., Fales, H.M., Gottesman, M.M., and Szakacs, G. (2009). Identification of compounds selectively killing multidrug-resistant cancer cells. Cancer Res. 69, 8293–8301.10.1158/0008-5472.CAN-09-2422Search in Google Scholar PubMed PubMed Central
Urbatsch, I.L., Gimi, K., Wilke-Mounts, S., and Senior, A.E. (2000). Investigation of the role of glutamine-471 and glutamine-1114 in the two catalytic sites of P-glycoprotein. Biochemistry 39, 11921–11927.10.1021/bi001220sSearch in Google Scholar PubMed
Wang, J., Grishin, N., Kinch, L., Cohen, J.C., Hobbs, H.H., and Xie, X.S. (2011). Sequences in the nonconsensus nucleotide-binding domain of ABCG5/ABCG8 required for sterol transport. J. Biol. Chem. 286, 7308–7314.10.1074/jbc.M110.210880Search in Google Scholar PubMed PubMed Central
Zaitseva, J., Jenewein, S., Jumpertz, T., Holland, I.B., and Schmitt, L. (2005). H662 is the linchpin of ATP hydrolysis in the nucleotide-binding domain of the ABC transporter HlyB. EMBO J. 24, 1901–1910.10.1038/sj.emboj.7600657Search in Google Scholar PubMed PubMed Central
Zolnerciks, J.K., Wooding, C., and Linton, K.J. (2007). Evidence for a Sav1866-like architecture for the human multidrug transporter P-glycoprotein. FASEB J. 21, 3937–3948.10.1096/fj.07-8610comSearch in Google Scholar PubMed
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