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Understanding transport by the major facilitator superfamily (MFS): structures pave the way

Nature Reviews Molecular Cell Biology volume 17, pages 123–132 (2016)Cite this article

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Abstract

Members of the major facilitator superfamily (MFS) of transport proteins are essential for the movement of a wide range of substrates across biomembranes. As this transport requires a series of conformational changes, structures of MFS transporters captured in different conformational states are needed to decipher the transport mechanism. Recently, a large number of MFS transporter structures have been determined, which has provided us with an unprecedented opportunity to understand general aspects of the transport mechanism. We propose an updated model for the conformational cycle of MFS transporters, the 'clamp-and-switch model', and discuss the role of so-called 'gating residues' and the substrate in modulating these conformational changes.

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Figure 1: Major facilitator superfamily (MFS) transporters: structures and basic principles.
Figure 2: Alternate access in major facilitator superfamily (MFS) transporters.
Figure 3: Gating.

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  1. Marger, M. D. & Saier, M. H. A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport. Trends Biochem. Sci. 18, 13–20 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Pao, S. S., Paulsen, I. T. & Saier, M. H. Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62, 1–34 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Reddy, V. S., Shlykov, M. A., Castillo, R., Sun, E. I. & Saier, M. H. The major facilitator superfamily (MFS) revisited. FEBS J. 279, 2022–2035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gray, K. A., Yates, B., Seal, R. L., Wright, M. W. & Bruford, E. A. Genenames.org: the HGNC resources in 2015. Nucleic Acids Res. 43, 1079–1085 (2015).

    Article  CAS  Google Scholar 

  5. Ren, Q., Chen, K. & Paulsen, I. T. TransportDB: a comprehensive database resource for cytoplasmic membrane transport systems and outer membrane channels. Nucleic Acids Res. 35, D274–D279 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Augustin, R. The protein family of glucose transport facilitators: it's not only about glucose after all. IUBMB Life 62, 315–333 (2010).

    CAS  PubMed  Google Scholar 

  7. Cura, A. J. & Carruthers, A. Role of monosaccharide transport proteins in carbohydrate assimilation, distribution, metabolism, and homeostasis. Compr. Physiol. 2, 863–914 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Smith, D. E., Clémençon, B. & Hediger, M. A. Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol. Aspects Med. 34, 323–336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Roth, M., Obaidat, A. & Hagenbuch, B. OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br. J. Pharmacol. 165, 1260–1287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hagenbuch, B. & Stieger, B. The SLCO (former SLC21) superfamily of transporters. Mol. Aspects Med. 34, 396–412 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Koepsell, H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34, 413–435 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Reimer, R. J. SLC17: a functionally diverse family of organic anion transporters. Mol. Aspects Med. 34, 350–359 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao, R. & Goldman, I. D. Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol. Aspects Med. 34, 373–385 (2013).

    Article  PubMed  CAS  Google Scholar 

  14. Hou, Z. & Matherly, L. H. Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr. Top. Membr. 73, 175–204 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Halestrap, A. P. & Wilson, M. C. The monocarboxylate transporter family — role and regulation. IUBMB Life 64, 109–119 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Lawal, H. O. & Krantz, D. E. SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol. Aspects Med. 34, 360–372 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hirabayashi, Y., Nomura, K. H. & Nomura, K. The acetyl-CoA transporter family SLC33. Mol. Aspects Med. 34, 586–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Chou, J. Y. & Mansfield, B. C. The SLC37 family of sugar-phosphate/phosphate exchangers. Curr. Top. Membr. 73, 357–382 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Drakesmith, H., Nemeth, E. & Ganz, T. Ironing out ferroportin. Cell Metab. 22, 777–787 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vitavska, O. & Wieczorek, H. The SLC45 gene family of putative sugar transporters. Mol. Aspects Med. 34, 655–660 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Bodoy, S., Fotiadis, D., Stoeger, C., Kanai, Y. & Palacín, M. The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol. Aspects Med. 34, 638–645 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Guan, L. & Kaback, H. R. Lessons from lactose permease. Annu. Rev. Biophys. Biomol. Struct. 35, 67–91 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Smirnova, I., Kasho, V. & Kaback, H. R. Lactose permease and the alternating access mechanism. Biochemistry 50, 9684–9693 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Kaback, H. R. A chemiosmotic mechanism of symport. Proc. Natl Acad. Sci. USA 112, 1259–1264 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abramson, J. et al. Structure and mechanism of the lactose permease of Escherichia coli. Science 301, 610–615 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Huang, Y., Lemieux, M. J., Song, J., Auer, M. & Wang, D.-N. Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 301, 616–620 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Yin, Y., He, X., Szewczyk, P., Nguyen, T. & Chang, G. Structure of the multidrug transporter EmrD from Escherichia coli. Science 312, 741–744 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dang, S. et al. Structure of a fucose transporter in an outward-open conformation. Nature 467, 734–738 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Newstead, S. et al. Crystal structure of a prokaryotic homologue of the mammalian oligopeptide-proton symporters, PepT1 and PepT2. EMBO J. 30, 417–426 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Heng, J. et al. Substrate-bound structure of the E. coli multidrug resistance transporter MdfA. Cell Res. 25, 1060–1073 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mirza, O., Guan, L., Verner, G., Iwata, S. & Kaback, H. R. Structural evidence for induced fit and a mechanism for sugar/H+ symport in LacY. EMBO J. 25, 1177–1183 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guan, L., Mirza, O., Verner, G., Iwata, S. & Kaback, H. R. Structural determination of wild-type lactose permease. Proc. Natl Acad. Sci. USA 104, 15294–15298 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chaptal, V. et al. Crystal structure of lactose permease in complex with an affinity inactivator yields unique insight into sugar recognition. Proc. Natl Acad. Sci. USA 108, 9361–9366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kumar, H. et al. Structure of sugar-bound LacY. Proc. Natl Acad. Sci. USA 111, 1784–1788 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kumar, H. et al. Structure of LacY with an α-substituted galactoside: connecting the binding site to the protonation site. Proc. Natl Acad. Sci. USA 112, 9004–9009 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Solcan, N. et al. Alternating access mechanism in the POT family of oligopeptide transporters. EMBO J. 31, 3411–3421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Doki, S. et al. Structural basis for dynamic mechanism of proton-coupled symport by the peptide transporter POT. Proc. Natl Acad. Sci. USA 110, 11343–11348 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Guettou, F. et al. Structural insights into substrate recognition in proton-dependent oligopeptide transporters. EMBO Rep. 14, 804–810 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lyons, J. et al. Structural basis for polyspecificity in the POT family of proton-coupled oligopeptide transporters. EMBO Rep. 15, 886–893 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guettou, F. et al. Selectivity mechanism of a bacterial homolog of the human drug-peptide transporters PepT1 and PepT2. Nat. Struct. Mol. Biol. 21, 728–731 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Zhao, Y. et al. Crystal structure of the E. coli peptide transporter YbgH. Structure 22, 1152–1160 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Fowler, P. W. et al. Gating topology of the proton-coupled oligopeptide symporters. Structure 23, 290–301 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huang, C.-Y. et al. In meso in situ serial X-ray crystallography of soluble and membrane proteins. Acta Crystallogr. D Biol. Crystallogr. 71, 1238–1256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Boggavarapu, R., Jeckelmann, J.-M., Harder, D., Ucurum, Z. & Fotiadis, D. Role of electrostatic interactions for ligand recognition and specificity of peptide transporters. BMC Biol. 13, 58 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Sun, L. et al. Crystal structure of a bacterial homologue of glucose transporters GLUT1–4. Nature 490, 361–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Quistgaard, E. M., Löw, C., Moberg, P., Trésaugues, L. & Nordlund, P. Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters. Nat. Struct. Mol. Biol. 20, 766–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Iancu, C. V., Zamoon, J., Woo, S. B., Aleshin, A. & Choe, J. Crystal structure of a glucose/H+ symporter and its mechanism of action. Proc. Natl Acad. Sci. USA 110, 17862–17867 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wisedchaisri, G., Park, M.-S., Iadanza, M. G., Zheng, H. & Gonen, T. Proton-coupled sugar transport in the prototypical major facilitator superfamily protein XylE. Nat. Commun. 5, 4521 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Deng, D. et al. Crystal structure of the human glucose transporter GLUT1. Nature 510, 121–125 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Deng, D. et al. Molecular basis of ligand recognition and transport by glucose transporters. Nature 526, 391–396 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Nomura, N. et al. Structure and mechanism of the mammalian fructose transporter GLUT5. Nature 526, 397–401 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yan, H. et al. Structure and mechanism of a nitrate transporter. Cell Rep. 3, 716–723 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Zheng, H., Wisedchaisri, G. & Gonen, T. Crystal structure of a nitrate/nitrite exchanger. Nature 497, 647–651 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fukuda, M. et al. Structural basis for dynamic mechanism of nitrate/nitrite antiport by NarK. Nat. Commun. 6, 7097 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Pedersen, B. P. et al. Crystal structure of a eukaryotic phosphate transporter. Nature 496, 533–536 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jiang, D. et al. Structure of the YajR transporter suggests a transport mechanism based on the conserved motif A. Proc. Natl Acad. Sci. USA 110, 14664–14669 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ethayathulla, A. S. et al. Structure-based mechanism for Na+/melibiose symport by MelB. Nat. Commun. 5, 3009 (2014).

    Article  PubMed  CAS  Google Scholar 

  58. Parker, J. L. & Newstead, S. Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1. Nature 507, 68–72 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sun, J. et al. Crystal structure of the plant dual-affinity nitrate transporter NRT1.1. Nature 507, 73–77 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Taniguchi, R. et al. Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat. Commun. 6, 8545 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Forrest, L. R., Krämer, R. & Ziegler, C. The structural basis of secondary active transport mechanisms. Biochim. Biophys. Acta 1807, 167–188 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Hirai, T. et al. Three-dimensional structure of a bacterial oxalate transporter. Nat. Struct. Biol. 9, 597–600 (2002).

    CAS  PubMed  Google Scholar 

  63. Yan, N. Structural advances for the major facilitator superfamily (MFS) transporters. Trends Biochem. Sci. 38, 151–159 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Jardetzky, O. Simple allosteric model for membrane pumps. Nature 211, 969–970 (1966).

    Article  CAS  PubMed  Google Scholar 

  65. Law, C. J., Maloney, P. C. & Wang, D.-N. Ins and outs of major facilitator superfamily antiporters. Annu. Rev. Microbiol. 62, 289–305 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Newstead, S. Molecular insights into proton coupled peptide transport in the PTR family of oligopeptide transporters. Biochim. Biophys. Acta 1850, 488–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Blodgett, D. M., De Zutter, J. K., Levine, K. B., Karim, P. & Carruthers, A. Structural basis of GLUT1 inhibition by cytoplasmic ATP. J. Gen. Physiol. 130, 157–168 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Krishnamurthy, H., Piscitelli, C. L. & Gouaux, E. Unlocking the molecular secrets of sodium-coupled transporters. Nature 459, 347–355 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Henderson, P. J. & Maiden, M. C. Homologous sugar transport proteins in Escherichia coli and their relatives in both prokaryotes and eukaryotes. Phil. Trans. R. Soc. 326, 391–410 (1990).

    CAS  Google Scholar 

  70. Yamaguchi, A., Someya, Y. & Sawai, T. Metal-tetracycline/H+ antiporter of Escherichia coli encoded by transposon Tn10: the role of a conserved sequence motif, GXXXXRXGRR, in a putative cytoplasmic loop between helices 2 and 3. J. Biol. Chem. 267, 19155–19162 (1992).

    Article  CAS  PubMed  Google Scholar 

  71. Jessen-Marshall, A. E., Paul, N. J. & Brooker, R. J. The conserved motif, GXXX(D/E)(R/K)XG[X](R/K)(R/K), in hydrophilic loop 2/3 of the lactose permease. J. Biol. Chem. 270, 16251–16257 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Frillingos, S., Sun, J., Gonzalez, A. & Kaback, H. R. Cysteine-scanning mutagenesis of helix II and flanking hydrophilic domains in the lactose permease of Escherichia coli. Biochemistry 36, 269–273 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Schürmann, A. et al. Role of conserved arginine and glutamate residues on the cytosolic surface of glucose transporters for transporter function. Biochemistry 36, 12897–12902 (1997).

    Article  PubMed  Google Scholar 

  74. Klingenberg, M. Transport viewed as a catalytic process. Biochimie 89, 1042–1048 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Motlagh, H. N., Wrabl, J. O., Li, J. & Hilser, V. J. The ensemble nature of allostery. Nature 508, 331–339 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Saier, M. H., Reddy, V. S., Tamang, D. G. & Västermark, Å. The transporter classification database. Nucleic Acids Res. 42, D251–D258 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Swedish Research Council (VR grant number: 621-2013-5905) and the Lundbeck foundation.

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Authors and Affiliations

  1. Esben M. Quistgaard is at the Department of Medical Biochemistry and Biophysics, Department of Molecular Biology and Genetics, Karolinska Institutet, Scheeles väg 2, SE-17177 Stockholm, Sweden, the MIND Centre, Aarhus University, Gustav Wieds Vej 10C, DK 8000 Aarhus C, Denmark, and the Center for Structural Systems Biology (CSSB), European Molecular Biology Laboratory, EMBL-Hamburg, c/o DESY, Building 25A, Notkestrasse 85, 22607, Hamburg, Germany.,

    Esben M. Quistgaard

  2. Christian Löw is at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17177 Stockholm, Sweden, and the Center for Structural Systems Biology (CSSB), European Molecular Biology Laboratory, EMBL-Hamburg, c/o DESY, Building 25A, Notkestrasse 85, 22607, Hamburg, Germany.,

    Christian Löw

  3. Fatma Guettou is at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17177 Stockholm, Sweden.,

    Fatma Guettou

  4. Pär Nordlund is at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17177 Stockholm, Sweden, and the School of Biological Sciences, Nanyang Technological University, 639798 Singapore, Singapore.,

    Pär Nordlund

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  1. Esben M. Quistgaard
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Correspondence to Esben M. Quistgaard or Pär Nordlund.

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Supplementary information

Supplementary information S1 (Figure)

Analysis of occluded MFS transporter structures. (PDF 2172 kb)

Supplementary information S2 (Figure)

Extended analysis of the role of the A-motifs in cytoplasmic gating. (PDF 586 kb)

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HUGO Gene Nomenclature Committee

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Transporter Classification Database

Protein Data Bank

4ZW9

1PV6

2GFP

3O7Q

4OAA

2Y5Y

2GFP

4M64

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Quistgaard, E., Löw, C., Guettou, F. et al. Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nat Rev Mol Cell Biol 17, 123–132 (2016). https://doi.org/10.1038/nrm.2015.25

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