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2.A.17 The Proton-dependent Oligopeptide Transporter (POT/PTR) Family

Proteins of the POT family (also called the PTR (peptide transport) family) consist of proteins from animals, plants, yeast, archaea and both Gram-negative and Gram-positive bacteria. Several of these organisms possess multiple POT family paralogues. The proteins are of about 450-600 amino acyl residues in length with the eukaryotic proteins in general being longer than the bacterial proteins. They exhibit 12 putative or established transmembrane α-helical spanners.  The plant homologues have been examined from phylogenetic standpoints (von Wittgenstein et al. 2014). 

Pairs of salt bridge interactions between transmembrane helices work in tandem to orchestrate alternating access transport within the PTR family (Newstead 2014). Key roles for residues conserved between bacterial and eukaryotic homologues suggest a conserved mechanism of peptide recognition and transport that in some cases has been subtly modified in individual species.  PepT1 and PepT2, mammalian members of this family, are responsible for the uptake of many pharmaceutically important drug molecules, including antibiotics and antiviral medications.  Thus, their promiscuity can be used for improving the oral bioavailability of poorly absorbed compounds (Newstead 2014).

While most members of the POT family catalyze peptide transport, one is a nitrate permease and one can transport histidine as well as peptides. A nitrate permease of Arabidopsis, Chl1 (TC #2.A.17.3.1), exhibits dual affinity. When phosphorylated at threonine-101, it exhibits high affinity (50 μM) for nitrate, but when not phosphorylated, it exhibits low affinity (~5 mM) (Liu and Tsay, 2003). Some of the peptide transporters can also transport antibiotics. They function by proton symport, but the substrate:H+ stoichiometry is variable: the high affinity rat PepT2 carrier catalyzes uptake of 2 and 3H+ with neutral and anionic dipeptides, respectively, while the low affinity PepT1 carrier catalyzes uptake of one H+ per neutral peptide. In eukaryotes, some of these transporters may be in organellar membranes such as the lysosomes.

Di- and tripeptide transporters of the POT/PTR/NRT1 family are localized either to the tonoplast (TP) or plasma membrane (PM). A 7 amino acid fragment of the hydrophilic N-terminal region of Arabidopsis PTR2, PTR4 and PTR6 is required for TP localization and sufficient to redirect not only PM-localized PTR1 or PTR5, but also sucrose transporter SUC2 to the tonopolast (Komarova et al., 2012). L(11) and I(12) of PTR2 are essential for TP targeting, while only one acidic amino acid at position 5, 6 or 7 is required, revealing a dileucine (LL or LI) motif with at least one upstream acidic residue. Similar dileucine motifs could be identified in other plant TP transporters. Targeting to the PM required the loop between transmembrane domains 6 and 7 of PTR1 or PTR5. Deletion of either PM or TP targeting signals resulted in retention in internal membranes, indicating that PTR trafficking to these destination membranes requires distinct signals and is in both cases not by default (Komarova et al., 2012).

The generalized transport reaction catalyzed by the proteins of the POT family is:

substrate (out) nH (out) → substrate (in) nH+ (in).


This family belongs to the: MFS Superfamily.

References associated with 2.A.17 family:

and Newstead S. (2015). Molecular insights into proton coupled peptide transport in the PTR family of oligopeptide transporters. Biochim Biophys Acta. 1850(3):488-99. 24859687
Andersen, T.G., H.H. Nour-Eldin, V.L. Fuller, C.E. Olsen, M. Burow, and B.A. Halkier. (2013). Integration of biosynthesis and long-distance transport establish organ-specific glucosinolate profiles in vegetative Arabidopsis. Plant Cell 25: 3133-3145. 23995084
Belmondo, S., V. Fiorilli, J. Pérez-Tienda, N. Ferrol, R. Marmeisse, and L. Lanfranco. (2014). A dipeptide transporter from the arbuscular mycorrhizal fungus Rhizophagus irregularis is upregulated in the intraradical phase. Front Plant Sci 5: 436. 25232358
Bippes, C.A., L. Ge, M. Meury, D. Harder, Z. Ucurum, H. Daniel, D. Fotiadis, and D.J. Müller. (2013). Peptide transporter DtpA has two alternate conformations, one of which is promoted by inhibitor binding. Proc. Natl. Acad. Sci. USA 110: E3978-3986. 24082128
Bucking, C. and P.M. Schulte. (2012). Environmental and nutritional regulation of expression and function of two peptide transporter (PepT1) isoforms in a euryhaline teleost. Comp Biochem Physiol A Mol Integr Physiol 161: 379-387. 22227314
Cai, H., M. Hauser, F. Naider, and J.M. Becker. (2007). Differential regulation and substrate preferences in two peptide transporters of Saccharomyces cerevisiae. Eukaryot. Cell. 6: 1805-1813. 17693598
Casagrande F., Harder D., Schenk A., Meury M., Ucurum Z., Engel A., Weitz D., Daniel H. and Fotiadis D. (2009). Projection structure of DtpD (YbgH), a prokaryotic member of the peptide transporter family. J Mol Biol. 394(4):708-17. 19782088
Chan, T., X. Lu, T. Shams, L. Zhu, M. Murray, and F. Zhou. (2016). The role of N-glycosylation in maintaining the transporter activity and expression of human Oligopeptide transporter 1 (hPepT1). Mol Pharm. [Epub: Ahead of Print] 27547863
Chen, X.-Z., T. Zhu, D.E. Smith, and M.A. Hediger. (1999). Stoichiometry and kinetics of the high-affinity H+-coupled peptide transporter PepT2. J. Biol. Chem. 274: 2773-2779. 9915809
Covitz, K.-M.Y., G.L. Amidon, and W. Sadée. (1998). Membrane topology of the human dipeptide transporter, hPEPT1, determined by epitope insertions. Biochemistry 37: 15214-15221. 9790685
Daniel, H. (1996). Function and molecular structure of brush border membrane peptide/H+ symporters. J. Membr. Biol. 154: 197-203. 8952949
Doki, S., H.E. Kato, N. Solcan, M. Iwaki, M. Koyama, M. Hattori, N. Iwase, T. Tsukazaki, Y. Sugita, H. Kandori, S. Newstead, R. Ishitani, and O. Nureki. (2013). Structural basis for dynamic mechanism of proton-coupled symport by the peptide transporter POT. Proc. Natl. Acad. Sci. USA 110: 11343-11348. 23798427
Döring, F., J. Will, S. Amasheh, W. Clauss, H. Ahlbrecht, and H. Daniel. (1998). Minimal molecular determinants of substrates for recognition by the intestinal peptide transporter. J. Biol. Chem. 273: 23211-23218. 9722551
Ernst, H.A., A. Pham, H. Hald, J.S. Kastrup, M. Rahman, and O. Mirza. (2009). Ligand binding analyses of the putative peptide transporter YjdL from E. coli display a significant selectivity towards dipeptides. Biochem. Biophys. Res. Commun. 389: 112-116. 19703419
Fan, X., H. Feng, Y. Tan, Y. Xu, Q. Miao, and G. Xu. (2015). A putative 6 trans-membrane nitrate transporter OsNRT1.1b plays a key role in rice under low nitrogen. J Integr Plant Biol. [Epub: Ahead of Print] 26220694
Fang, G., W.N. Konings, and B. Poolman. (2000). Kinetics and substrate specificity of membrane-reconstituted peptide transporter DtpT of Lactococcus lactis. J. Bacteriol. 182: 2530-2535. 10762255
Fei, Y.-J., T. Fujita, D.F. Lapp, V. Ganapathy, and F.H. Leibach. (1998). Two oligopeptide transporters from Caenorhabditis elegans: molecular cloning and functional expression. Biochem. J. 322: 565-572. 9601088
Frommer, W.B., S. Hummel, and D. Rentsch. (1994). Cloning of an Arabidopsis histidine transporting protein related to nitrate and peptide transporters. FEBS Lett. 347: 185-189. 8033999
Gabrielsen, M., F. Kroner, I. Black, N.W. Isaacs, A.J. Roe, and K. McLuskey. (2011). High-throughput identification of purification conditions leads to preliminary crystallization conditions for three inner membrane proteins. Mol. Membr. Biol. 28: 445-453. 22034843
Geissler, S., M. Zwarg, I. Knütter, F. Markwardt, and M. Brandsch. (2010). The bioactive dipeptide anserine is transported by human proton-coupled peptide transporters. FEBS J. 277: 790-795. 20067523
Guettou, F., E.M. Quistgaard, L. Trésaugues, P. Moberg, C. Jegerschöld, L. Zhu, A.J. Jong, P. Nordlund, and C. Löw. (2013). Structural insights into substrate recognition in proton-dependent oligopeptide transporters. EMBO Rep 14: 804-810. 23867627
Hagting, A., E.R.S. Kunji, K.J. Leenhouts, B. Poolman, and W.N. Konings. (1994). The di- and tripeptide transport protein of Lactococcus lactis. J. Biol. Chem. 269: 11391-11399. 8157671
Hagting, A., J.v.d. Velde, B. Poolman and W.N. Konings (1997). Membrane topology of the di- and tripeptide transport protein of Lactococcus lactis. Biochemistry 36: 6777-6785. 9184160
Harder, D., J. Stolz, F. Casagrande, P. Obrdlik, D. Weitz, D. Fotiadis, and H. Daniel. (2008). DtpB (YhiP) and DtpA (TppB, YdgR) are prototypical proton-dependent peptide transporters of Escherichia coli. FEBS J. 275: 3290-3298. 18485005
Jensen JM., Aduri NG., Prabhala BK., Jahnsen R., Franzyk H. and Mirza O. (2014). Critical role of a conserved transmembrane lysine in substrate recognition by the proton-coupled oligopeptide transporter YjdL. Int J Biochem Cell Biol. 55:311-7. 25261786
Kanno, Y., Y. Kamiya, and M. Seo. (2013). Nitrate does not compete with abscisic acid as a substrate of AtNPF4.6/NRT1.2/AIT1 in Arabidopsis. Plant Signal Behav 8: e26624. 24084651
Karim, S., D. Lundh, K.O. Holmström, A. Mandal, and M. Pirhonen. (2005). Structural and functional characterization of AtPTR3, a stress-induced peptide transporter of Arabidopsis. J Mol Model 11: 226-236. 15889294
Karim, S., K.O. Holmström, A. Mandal, P. Dahl, S. Hohmann, G. Brader, E.T. Palva, and M. Pirhonen. (2007). AtPTR3, a wound-induced peptide transporter needed for defence against virulent bacterial pathogens in Arabidopsis. Planta 225: 1431-1445. 17143616
Knütter, I., B. Hartrodt, G. Tóth, A. Keresztes, G. Kottra, C. Mrestani-Klaus, I. Born, H. Daniel, K. Neubert, and M. Brandsch. (2007). Synthesis and characterization of a new and radiolabeled high-affinity substrate for H+/peptide cotransporters. FEBS J. 274(22):5905-5914. 17944948
Komarova NY., Meier S., Meier A., Grotemeyer MS. and Rentsch D. (2012). Determinants for Arabidopsis peptide transporter targeting to the tonoplast or plasma membrane. Traffic. 13(8):1090-105. 22537078
Komarova, N.Y., K. Thor, A. Gubler, S. Meier, D. Dietrich, A. Weichert, M. Suter Grotemeyer, M. Tegeder, and D. Rentsch. (2008). AtPTR1 and AtPTR5 transport dipeptides in planta. Plant Physiol. 148: 856-869. 18753286
Kottra, G., A. Stamfort, and H. Daniel. (2002). PEPT1 as a paradigm for membrane carriers that mediate electrogenic bidirectional transport of anionic, cationic, and neutral substrates. J. Biol. Chem. 277: 32683-32691. 12082113
Leibach, F.H. and V. Ganapathy. (1996). Peptide transporters in the intestine and the kidney. Annu. Rev. Nutr. 16: 99-119. 8839921
Liu, K.H. and Y.F. Tsay. (2003). Switching between the two action modes of the dual-affinity nitrate transporter CHL1 by phosphorylation. EMBO. J. 22: 1005-1013. 12606566
M Jensen J., A Ernst H., Wang X., Hald H., C Ditta A., Ismat F., Rahman M. and Mirza O. (2012). Functional Investigation of Conserved Membrane-Embedded Glutamate Residues in the Proton-Coupled Peptide Transporter YjdL. Protein Pept Lett. 19(3):282-7. 21933132
Martín, Y., F.J. Navarro, and J.M. Siverio. (2008). Functional characterization of the Arabidopsis thaliana nitrate transporter CHL1 in the yeast Hansenula polymorpha. Plant Mol. Biol. 68: 215-224. 18563586
Miyamoto, K.-I., T. Shiraga, K. Morita, H. Yamamoto, H. Haga, Y. Taketani, I. Tamai, Y. Sai, A. Tsuji, and E. Takeda. (1996). Sequence, tissue distribution and developmental changes in rat intestinal oligopeptide transporter. Biochim. Biophys. Acta 1305: 34-38. 8605246
Newstead, S., D. Drew, A.D. Cameron, V.L. Postis, X. Xia, P.W. Fowler, J.C. Ingram, E.P. Carpenter, M.S. Sansom, M.J. McPherson, S.A. Baldwin, and S. Iwata. (2011). Crystal structure of a prokaryotic homologue of the mammalian oligopeptide-proton symporters, PepT1 and PepT2. EMBO. J. 30: 417-426. 21131908
Nour-Eldin, H.H., T.G. Andersen, M. Burow, S.R. Madsen, M.E. Jørgensen, C.E. Olsen, I. Dreyer, R. Hedrich, D. Geiger, and B.A. Halkier. (2012). NRT/PTR transporters are essential for translocation of glucosinolate defence compounds to seeds. Nature 488: 531-534. 22864417
Paulsen, I.T. and R.A. Skurray. (1994). The POT family of transport proteins. Trends in Biochem. Sci. 18: 404. 7817396
Pieri, M., C. Gan, P. Bailey, and D. Meredith. (2009). The transmembrane tyrosines Y56, Y91 and Y167 play important roles in determining the affinity and transport rate of the rabbit proton-coupled peptide transporter PepT1. Int J Biochem. Cell Biol. 41: 2204-2213. 19389486
Romano, A., G. Kottra, A. Barca, N. Tiso, M. Maffia, F. Argenton, H. Daniel, C. Storelli, and T. Verri. (2005). High-affinity peptide transporter PEPT2 (SLC15A2) of the zebrafish Danio rerio: functional properties, genomic organization, and expression analysis. Physiol Gen. 24: 207-217. 16317081
Rubio-Aliaga, I., M. Boll, and H. Daniel. (2000). Cloning and Characterization of the Gene Encoding the Mouse Peptide Transporter PEPT2. Biochem. and Biophys. Research Communications 276: 734-741. 11027540
Saier, M.H., Jr., B.H. Eng, S. Fard, J. Garg, D.A. Haggerty, W.J. Hutchinson, D.L. Jack, E.C. Lai, H.J. Liu, D.P. Nusinew, A.M. Omar, S.S. Pao, I.T. Paulsen, J.A. Quan, M. Sliwinski, T.-T. Tseng, S. Wachi, and G.B. Young. (1999). Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim. Biophys. Acta 1422: 1-56. 10082980
Segonzac, C., J.C. Boyer, E. Ipotesi, W. Szponarski, P. Tillard, B. Touraine, N. Sommerer, M. Rossignol, and R. Gibrat. (2007). Nitrate efflux at the root plasma membrane: identification of an Arabidopsis excretion transporter. Plant Cell. 19: 3760-3777. 17993627
Solcan N., Kwok J., Fowler PW., Cameron AD., Drew D., Iwata S. and Newstead S. (2012). Alternating access mechanism in the POT family of oligopeptide transporters. EMBO J. 31(16):3411-21. 22659829
Sreedharan, S., O. Stephansson, H.B. Schiöth, and R. Fredriksson. (2011). Long evolutionary conservation and considerable tissue specificity of several atypical solute carrier transporters. Gene 478: 11-18. 21044875
Steiner, H.-Y., F. Naider, and J.M. Becker. (1995). The PTR family: a new group of peptide transporters. Mol. Microbiol. 16: 825-834. 7476181
Steiner, H.-Y., W. Song, L. Zhang, F. Naider, J.M. Becker, and G. Stacey. (1994). An arabidopsis peptide transporter is a member of a new class of membrane transport proteins. Plant Cell 6: 1289-1299. 7919993
Sugiura, M., M.N. Georgescu, and M. Takahashi. (2007). A nitrite transporter associated with nitrite uptake by higher plant chloroplasts. Plant Cell Physiol. 48: 1022-1035. 17566055
Sun, J. and N. Zheng. (2015). Molecular Mechanism Underlying the Plant NRT1.1 Dual-Affinity Nitrate Transporter. Front Physiol 6: 386. 26733879
Søndergaard, H.B., B. Brodin, and C.U. Nielsen. (2008). HPEPT1 is responsible for uptake and transport of Gly-Sar in the human bronchial airway epithelial cell-line Calu-3. Pflugers Arch 456(3): 611-622. 18094991
Tsay, Y.-F., J.I. Schroeder, K.A. Feldmann, and N.M. Crawford. (1993). The herbicide sensitivity gene CHL1 of Arabidopsis encodes a nitrate-inducible nitrate transporter. Cell 72: 705-713. 8453665
Verri, T., A. Barca, P. Pisani, B. Piccinni, C. Storelli, and A. Romano. (2016). Di- and tripeptide transport in vertebrates: the contribution of teleost fish models. J Comp Physiol B. [Epub: Ahead of Print] 27803975
von Wittgenstein, N.J., C.H. Le, B.J. Hawkins, and J. Ehlting. (2014). Evolutionary classification of ammonium, nitrate, and peptide transporters in land plants. BMC Evol Biol 14: 11. 24438197
Weitz, D., D. Harder, F. Casagrande, D. Fotiadis, P. Obrdlik, B. Kelety, and H. Daniel. (2007). Functional and structural characterization of a prokaryotic peptide transporter with features similar to mammalian PEPT1. J. Biol. Chem. 282: 2832-2839. 17158458
Wu, M., S. Tong, S. Waltersperger, K. Diederichs, M. Wang, and L. Zheng. (2013). Crystal structure of Ca2+/H+ antiporter protein YfkE reveals the mechanisms of Ca2+ efflux and its pH regulation. Proc. Natl. Acad. Sci. USA 110: 11367-11372. 23798403
Xu, L., Y. Li, I.S. Haworth, and D.L. Davies. (2010). Functional role of the intracellular loop linking transmembrane domains 6 and 7 of the human dipeptide transporter hPEPT1. J. Membr. Biol. 238: 43-49. 21104182
Zhao, Y., G. Mao, M. Liu, L. Zhang, X. Wang, and X.C. Zhang. (2014). Crystal structure of the E. coli peptide transporter YbgH. Structure 22: 1152-1160. 25066136
Zhou, J.-J., F.L. Theodoulou, I. Muldin, B. Ingemarsson, and A.J. Miller. (1998). Cloning and functional characterization of a Brassica napus transporter that is able to transport nitrate and histidine. J. Biol.Chem. 273: 12017-12023. 9575142
Zhou, X., M. Thamotharan, A. Gangopadhyay, C. Serdikoff, and S.A. Adibi. (2000). Characterization of an oligopeptide transporter in renal lysosomes. Biochim. Biophys. Acta 1466: 372-378. 10825457