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2.A.18 The Amino Acid/Auxin Permease (AAAP) Family

The AAAP family includes hundreds of proteins from plants, animals, yeast and fungi. Individual permeases of the AAAP family transport auxin (indole-3-acetic acid), a single amino acid or multiple amino acids. Some of these permeases exhibit very broad specificities transporting all twenty amino acids naturally found in proteins. Some also transport D-amino acids. There are 7 AAAP paralogues in Saccharomyces cerevisiae, at least 9 in Arabidopsis thaliana and at least 5 in Caenorhabditis elegans. Six AAPs in A. thaliana transport neutral and charged amino acids with varying specificities and affinities (Fischer et al., 2002). All transport neutral amino acids and some acidic amino acids, always with just one proton. AAP3 and AAP5 are the only ones transporting basic amino acids, and only AAP6 transports aspartate (Fischer et al., 2002).

AAAP family proteins, all from eukaryotes, vary from 376 to 713 amino acyl residues in length, but most are of 400-500 residues. Most of the size variation occurs as a result of the presence of long N-terminal hydrophilic extensions in some of the proteins. Some of the yeast proteins are particularly long. Variation in the loops and the C-termini also occurs. These proteins exhibit 11 (or 10) putative transmembrane α-helical spanners. One homologue, AAP1 of A. thaliana (TC #2.A.18.2.1), has 11 established TMSs (Chang and Bush, 1997).

Members of the AAAP family exhibit limited sequence similarity with members of the large APC family (TC #2.A.3). Thus, the AAAP family may be distantly related to the APC family.

Among animal AAAP family members are numerous growth regulating System A and System N isoforms, each exhibiting distinctive tissue and subcellular localizations. The different isoforms also exhibit different relative affinities for the amino acid substrates. Some catalyze H+ antiport and can function bidirectionally. Since Systems A are electrogenic which Systems N are not, the amino acid:cation stoichiometries may differ (Chaudhry et al., 2001, 2002; Varoqui et al., 2000).

Six auxin/amino acid permeases (AAAPs) from Arabidopsis mediate transport of a wide spectrum of amino acids (Fischer et al., 2002). AAAPs are distantly related to plasma membrane amino acid transport systems N and A and to vesicular transporters such as VGAT from mammals. Although capable of recognizing and transporting a wide spectrum of amino acids, individual AAAPs differ with respect to specificity. Apparent substrate affinities are influenced by structure and net charge and vary by three orders of magnitude (Fischer et al., 2002). AAAPs mediate cotransport of neutral amino acids with one proton, and uncharged forms of acidic and basic amino acids are cotransported with one proton. Since all AAAPs are differentially expressed, different tissues may be supplied with a different spectrum of amino acids.

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

Substrate (out) + nH+ (out) → Substrate (in) + nH+ (in)

This family belongs to the: APC Superfamily.

References associated with 2.A.18 family:

Anderson, C.M., A. Howard, J.R. Walters, V. Ganapathy, and D.T. Thwaites. (2009). Taurine uptake across the human intestinal brush-border membrane is via two transporters: H+-coupled PAT1 (SLC36A1) and Na+- and Cl--dependent TauT (SLC6A6). J. Physiol. 587: 731-744. 19074966
Aubrey, K.R., F.M. Rossi, R. Ruivo, S. Alboni, G.C. Bellenchi, A. Le Goff, B. Gasnier, and S. Supplisson. (2007). The transporters GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype. J. Neurosci. 27: 6273-6281. 17554001
Balkrishna, S., A. Bröer, A. Kingsland, and S. Bröer. (2010). Rapid downregulation of the rat glutamine transporter SNAT3 by a caveolin-dependent trafficking mechanism in Xenopus laevis oocytes. Am. J. Physiol. Cell Physiol. 299: C1047-1057. 20739622
Bennett, M.J., A. Marchant, H.G. Green, S.T. May, S.P. Ward, P.A. Millner, A.R. Walker, B. Schulz, and K.A. Feldmann. (1996). Arabidopsis AUX1 gene: a permease-like regulator of root gravitropism. Science 273: 948-950. 8688077
Bock, K.W., D. Honys, J.M. Ward, S. Padmanaban, E.P. Nawrocki, K.D. Hirschi, D. Twell, and H. Sze. (2006). Integrating membrane transport with male gametophyte development and function through transcriptomics. Plant Physiol. 140: 1151-1168. 16607029
Boll, M., H. Daniel, and B. Gasnier. (2004). The SLC36 family: proton-coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis. Pflugers Arch 447: 776-779. 12748860
Boll, M., M. Foltz, I. Rubio-Aliaga, G. Kottra, and H. Daniel. (2002). Functional characterization of two novel mammalian electrogenic proton-dependent amino acid cotransporters. J. Biol. Chem. 277: 22966-22973. 11959859
Bröer, S. (2008). Amino acid transport across mammalian intestinal and renal epithelia. Physiol. Rev. 88: 249-286. 18195088
Carraro, N., T.E. Tisdale-Orr, R.M. Clouse, A.S. Knöller, and R. Spicer. (2012). Diversification and Expression of the PIN, AUX/LAX, and ABCB Families of Putative Auxin Transporters in Populus. Front Plant Sci 3: 17. 22645571
Chang, H.C. and D.R. Bush. (1997). Topology of NAT2 (AAP1): a prototypical example of a new family of amino acid transporters. J. Biol. Chem. 272: 30552-30557. 9374550
Chardwiriyapreecha S., Mukaiyama H., Sekito T., Iwaki T., Takegawa K. and Kakinuma Y. (2010). Avt5p is required for vacuolar uptake of amino acids in the fission yeast Schizosaccharomyces pombe. FEBS Lett. 584(11):2339-45. 20388511
Chaudhry, F.A., D. Krizaj, P. Larsen, R.J. Reimer, J. Storm-Mathiesen, D.R. Copenhagen, M.P. Kavanaugh, and R.H. Edwards. (2001). Coupled and uncoupled proton movement regulates amino acid transport by System N. EMBO J. 20: 7041-7051. 11742981
Chaudhry, F.A., D. Schmitz, R.J. Reimer, P. Larsson, A.T. Gray, R. Nicoll, M. Kavanaugh, and R.H. Edwards. (2002). Glutamine uptake by neurons: interaction of protons with system A transporters. J. Neurosci. 22: 62-72. 11756489
Chen, L. and D.R. Bush. (1997). LHT1, a lysine- and histidine-specific amino acid transporter in arabidopsis. Plant Physiol. 115: 1127-1134. 9390441
Dorn M., Weiwad M., Markwardt F., Laug L., Rudolph R., Brandsch M. and Bosse-Doenecke E. (2009). Identification of a disulfide bridge essential for transport function of the human proton-coupled amino acid transporter hPAT1. J Biol Chem. 284(33):22123-32. 19549785
Fei, Y., M. Sugawara, T. Nakanishi, W. Huang, H. Wang, P.D. Prasad, F.H. Leibach, and V. Ganapathy. (2000). Primary structure, genomic organization, and functional and electrogenic characteristics of human system N1, a Na+- and H+-coupled glutamine transporter. J. Biol. Chem. 275: 23707-23717. 10823827
Fischer, W-N., M. Kwart, S. Hummel, and W.B. Frommer. (1995). Substrate specificity and expression profile of amino acid transporters (AAPs) in Arabidopsis. J. Biol. Chem. 270: 16315-16320. 7608199
Fischer, W.N., D.D. Loo, W. Koch, U. Ludewig, K.J. Boorer, M. Tegeder, D. Rentsch, E.M. Wright, and W.B. Frommer. (2002). Low and high affinity amino acid H+-cotransporters for cellular import of neutral and charged amino acids. Plant J. 29: 717-731. 12148530
Gasnier, B. (2004). The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch 447: 756-759. 12750892
Goberdhan, D.C., D. Meredith, C.A. Boyd, and C. Wilson. (2005). PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Development. 132: 2365-2375. 15843412
Gu, S., H.L. Roderick, P. Camacho, and J.X. Jiang. (2000). Identification and characterization of an amino acid transporter expressed differentially in liver. Proc. Natl. Acad. Sci. USA 97: 3230-3235. 10716701
Hatanaka, T., W. Huang, H. Wang, M. Sugawara, P.D. Prasad, F.H. Leibach, and V. Ganapathy. (2000). Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of amino acid transport system A. Biochim. Biophys. Acta 1467: 1-6. 10930503
Hatanaka, T., Y. Hatanaka, and M. Setou. (2006b). Regulation of amino acid transporter ATA2 by ubiquitin ligase Nedd4-2. J. Biol. Chem. 281: 35922-35930. 17003038
Hatanaka, T., Y. Hatanaka, J. Tsuchida, V. Ganapathy, and M. Setou. (2006a). Amino acid transporter ATA2 is stored at the trans-Golgi network and released by insulin stimulus in adipocytes. J. Biol. Chem. 281: 39273-39284. 17050538
Hyde, R., E.L. Cwiklinski, K. MacAulay, P.M. Taylor, and H.S. Hundal. (2007). Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability. J. Biol. Chem. 282: 19788-19798. 17488712
Juge, N., A. Muroyama, M. Hiasa, H. Omote, and Y. Moriyama. (2009). Vesicular inhibitory amino acid transporter is a Cl-/γ-aminobutyrate Co-transporter. J. Biol. Chem. 284: 35073-35078. 19843525
McIntire, S.L., R.J. Reimer, K. Schuske, R.H. Edwards, and E.M. Jorgensen. (1997). Identification and characterization of the vesicular GABA transporter. Nature 389: 870-876. 9349821
Miyauchi, S., E.L. Abbot, L. Zhuang, R. Subramanian, V. Ganapathy, and D.T. Thwaites. (2005). Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Mol. Membr. Biol. 22: 549-559. 16373326
Nakanishi, T., R. Kekuda, Y.J. Fei, T. Hatanaka, M. Sugawara, R.G. Martindale, F.H. Leibach, P.D. Prasad, and V. Ganapathy. (2001). Cloning and functional characterization of a new subtype of the amino acid transport system N. Am. J. Physiol. Cell Physiol. 281: C1757-1768. 11698233
Okumoto, S., R. Schmidt, M. Tegeder, W.N. Fischer, D. Rentsch, W.B. Frommer, and W. Koch. (2002). High affinity amino acid transporters specifically expressed in xylem parenchyma and developing seeds of Arabidopsis. J. Biol. Chem. 277: 45338-45346. 12244056
Reimer, R.J., F.A. Chaudhury, A.T. Gray, and R.H. Edwards. (2000). Amino acid transport System A resembles System N in sequence but differs in mechanism. Proc. Natl. Acad. Sci. USA 97: 7715-7720. 10859363
Reinhardt, D., E.-R. Pesce, P. Stieger, T. Mandel, K. Baltensperger, M. Bennett, J. Traas, J. Friml, and C. Kuhlemeier. (2003). Regulation of phyllotaxis by polar auxin transport. Nature 426: 255-260. 14628043
Rentsch, D., B. Hirner, E. Schmeizer, and W.B. Frommer. (1996). Salt stress-induced proline transporters and salt stress-repressed broad specificity amino acid permeases identified by suppression of a yeast amino acid permease-targeting mutant. Plant Cell 8: 1437-1446. 8776904
Rubio-Aliaga, I., M. Boll, D.M.V. Weisenhorn, M. Foltz, G. Kottra, and H. Daniel. (2004). The proton/amino acid cotransporter PAT2 is expressed in neurons with a different subcellular localization than its paralog PAT1. J. Biol. Chem. 279: 2754-2760. 14600155
Russnak, R., D. Konczal, and S.L. McIntire. (2001). A family of yeast proteins mediating bidirectional vacuolar amino acid transport. J. Biol. Chem. 276: 23849-23857. 11274162
Shaked-Mishan, P., M. Suter-Grotemeyer, T. Yoel-Almagor, N. Holland, D. Zilberstein, and D. Rentsch D. (2006). A novel high-affinity arginine transporter from the human parasitic protozoan Leishmania donovani. Mol. Microbiol. 60: 30-38. 16556218
Shi, Q., R. Padmanabhan, C.J. Villegas, S. Gu, and J.X. Jiang. (2011). Membrane Topological Structure of Neutral System N/A Amino Acid Transporter 4 (SNAT4) Protein. J. Biol. Chem. 286: 38086-38094. 21917917
Sugawara, M., T. Nakanishi, Y.J. Fei, R.G. Martindale, M.E. Ganapathy, F.H. Leibach, and V. Ganapathy. (2000). Structure and function of ATA3, a new subtype of amino acid transport system A, primarily expressed in the liver and skeletal muscle. Biochim. Biophys. Acta. 1509: 7-13. 11118514
Sugawara, M., T. Nakanishi, Y.J. Fei, W. Huang, M.E. Ganapathy, F.H. Leibach, and V. Ganapathy. (2000). Cloning of an amino acid transporter with functional characteristics and tissue expression pattern identical to that of system A. J. Biol. Chem. 275: 16473-16477. 10747860
Thwaites, D.T. and C.M. Anderson. (2011). The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol 164: 1802-1816. 21501141
Trip, H., M.E. Evers, and A.J.M. Driessen. (2004). PcMtr, an aromatic and neutral aliphatic amino acid permease of Penicillium chrysogenum. Biochim. Biophys. Acta 1667: 167-173. 15581852
Tsitsiou E., Sibley CP., D'Souza SW., Catanescu O., Jacobsen DW. and Glazier JD. (2009). Homocysteine transport by systems L, A and y+L across the microvillous plasma membrane of human placenta. J Physiol. 587(Pt 16):4001-13. 19564394
Varoqui, H., H. Zhu, D. Yao, H. Ming, and J.D. Erickson. (2000). Cloning and functional identification of a neuronal glutamine transporter. J. Biol. Chem. 275: 4049-4054. 10660562
Voigt, V., L. Laug, K. Zebisch, I. Thondorf, F. Markwardt, and M. Brandsch. (2013). Transport of the areca nut alkaloid arecaidine by the human proton-coupled amino acid transporter 1 (hPAT1). J Pharm Pharmacol 65: 582-590. 23488788
Williams, L.E. and A.J. Miller. (2001). Transporters responsible for the uptake and partitioning of nitrogenous solutes. Annu. Rev. Plant Physiol. Plant Mol. Biol. 52: 659-688. 11337412
Wipf, D., U. Ludewig, M. Tegeder, D. Rentsch, W. Koch, and W.B. Frommer. (2002). Conservation of amino acid transporters in fungi, plants and animals. Trends Biochem. Sci. 27: 139-147. 11893511
Yao, D., B. Mackenzie, H. Ming, H. Varoqui, H. Zhu, M.A. Hediger, and J.D. Erickson. (2000). A novel system A isoform mediating Na+/neutral amino acid cotransport. J. Biol. Chem. 275: 22790-22797. 10811809
Young, G.B., D.L. Jack, D.W. Smith, and M.H. Saier, Jr. (1999). The amino acid/auxin:proton symport permease family. Biochim. Biophys. Acta 1415: 306-322. 9889387
Zhang, Z. and C. Grewer. (2007). The sodium-coupled neutral amino acid transporter SNAT2 mediates an anion leak conductance that is differentially inhibited by transported substrates. Biophys. J. 92: 2621-2632. 17237199
Zhang, Z., C.B. Zander, and C. Grewer. (2011). The C-terminal domain of the neutral amino acid transporter SNAT2 regulates transport activity through voltage-dependent processes. Biochem. J. 434: 287-296. 21158741