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The ancillary proteins of HATs: SLC3 family of amino acid transporters

  • The ABC of Solute Carriers
  • Guest Editor: Matthias A. Hediger
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Abstract

The heteromeric amino acid transporters (HATs) are composed of a light and a heavy subunit linked by a disulfide bridge. The heavy subunits are the SLC3 members (rBAT and 4F2hc), whereas the light subunits are members of the SLC7 family of amino acid transporters. SLC3 proteins are type II membrane glycoproteins (i.e., one single transmembrane domain and the C-terminus located outside the cell) with a bulky extracellular domain that shows homology with α-glucosidases. rBAT heterodimerizes with b0,+AT (SLC7A9) constituting the amino acid transport b0,+, the main system responsible for the apical reabsorption of cystine in kidney. The defect in this system causes cystinuria, the most common primary inherited aminoaciduria. 4F2hc subserves various amino acid transport systems by dimerization with different SLC7 proteins. The main role of SLC3 proteins is to help routing of the holotransporter to the plasma membrane. A working model for the biogenesis of HATs based on recent data on the rBAT/b0,+AT heterodimeric complex is presented. 4F2hc is a multifunctional protein, and in addition to its role in amino acid transport, it may be involved in other cellular functions. Studies on two SLC7 members (Asc-2 and AGT1) demonstrate heterodimerization with unknown heavy subunits.

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References

  1. Bauch C, Verrey F (2002) Apical hetero dimeric cystine and cationic amino acid transporter expressed in MDCK cells. Am J Physiol283:F181–F189

    Google Scholar 

  2. Bauch C, Forster N, Loffing-Cueni D, Summa V, Verrey F (2003) Functional cooperation of epithelial heteromeric amino acid transporters expressed in Madin-Darby canine kidney cells. J Biol Chem 278:1316–1322

    Article  CAS  PubMed  Google Scholar 

  3. Bertran J, Magagnin S, Werner A, Markovich D, Biber J, Testar X, Zorzano A, Kuhn LC, Palacín M, Murer H (1992) Stimulation of system y(+)-like amino acid transport by the heavy chain of human 4F2 surface antigen in Xenopus laevis oocytes. Proc Natl Acad Sci USA 89:5606–5610

    CAS  PubMed  Google Scholar 

  4. Bertran J, Werner A, Moore ML, Stange G, Markovich D, Biber J, Testar X, Zorzano A, Palacín M, Murer H (1992) Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic and neutral amino acids. Proc Natl Acad Sci USA 89:5601–5605

    CAS  PubMed  Google Scholar 

  5. Bertran J, Werner A, Chillaron J, Nunes V, Biber J, Testar X, Zorzano A, Estivill X, Murer H, Palacín M (1993) Expression cloning of a human renal cDNA that induces high affinity transport of l-cystine shared with dibasic amino acids in Xenopus oocytes. J Biol Chem 268:14842–14849

    CAS  PubMed  Google Scholar 

  6. Broer A, Friedrich B, Wagner CA, Fillon S, Ganapathy V, Lang F, Broer S (2001) Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains. Biochem J 355:725–731

    CAS  PubMed  Google Scholar 

  7. Calonge MJ, Gasparini P, Chillarón J, Chillón M, Gallucci M, Rousaud F, Zelante L, Testar X, Dallapiccola B, Di Silverio F, Barceló P, Estivill X, Zorzano A, Nunes V, Palacín M (1994) Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet 6:420–425

    CAS  PubMed  Google Scholar 

  8. Calonge MJ, Volpini V, Bisceglia L, Rousaud F, Sanctis L de, Beccia E, Zelante L, Testar X, Zorzano A, Estivill X, Gasparini P, Nunes V, Palacín M (1995) Genetic heterogeneity in cystinuria: the rBAT gene is linked to type I but not to type III cystinuria. Proc Natl Acad Sci USA 92:9667–9671

    CAS  PubMed  Google Scholar 

  9. Chairoungdua A, Segawa H, Kim JY, Miyamoto K, Haga H, Fukui Y, Mizoguchi K, Ito H, Takeda E, Endou H, Kanai Y (1999) Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein. J Biol Chem 274:28845–28848

    Google Scholar 

  10. Chairoungdua A, KanaiY, Matsuo H, Inatomi J Kim DK, Endou H (2001) Identification and characterization of a novel member of the heterodimeric amino acid transporter family presumed to be associated with an unknown heavy chain. J Biol Chem 276:49390–49399

    CAS  PubMed  Google Scholar 

  11. Chillarón J, Estévez R, Mora C, Wagner CA, Suessbrich H, Lang F, Gelpi JL, Testar X, Busch AE, Zorzano A, Palacín M (1996) Obligatory amino acid exchange via systems b0,+-like and y+L-like. A tertiary active transport mechanism for renal reabsorption of cystine and dibasic amino acids. J Biol Chem 271:17761–17770

    Article  PubMed  Google Scholar 

  12. Chillarón J, Roca R, Valencia A, Zorzano A, Palacín M (2001) Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am J Physiol 281:F995–F1018

    Google Scholar 

  13. Dello Strologo L, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, Sanctis L de, Ponzone A, Gallucci M, Bisceglia L, Zelante L, Jimenez-Vidal M, Font M, Zorzano A, Rousaud F, Nunes V, Gasparini P, Palacín M, Rizzoni G (2002) Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol 13:2547–2553

    PubMed  Google Scholar 

  14. Deves R, Boyd CA (2000) Surface antigen CD98(4F2): not a single membrane protein, but a family of proteins with multiple functions J Membr Biol 173:165–177

    Google Scholar 

  15. Deves R, Chavez P, Boyd CA (1992) Identification of a new transport system (y+L) in human erythrocytes that recognizes lysine and leucine with high affinity. J Physiol (Lond) 454:491–501

    Google Scholar 

  16. Estévez R, Camps M, Rojas AM, Testar X, Devés R, Hediger MA, Zorzano A, Palacín M (1998) The amino acid transport system y+L/4F2hc is a heteromultimeric complex. FASEB J 12:1319–1329

    PubMed  Google Scholar 

  17. Fenczik CA, Sethi T, Ramos JW, Hughes PE, Ginsberg MH (1997) Complementation of dominant suppression implicates CD98 in integrin activation. Nature 390:81–85

    Article  CAS  PubMed  Google Scholar 

  18. Fenczik CA, Zent R, Dellos M, Calderwood DA, Satriano J, Kelly C, Ginsberg MH (2001) Distinct domains of CD98hc regulate integrins and amino acid transport. J Biol Chem 276:8746–8752

    Article  CAS  PubMed  Google Scholar 

  19. Fernández E, Carrascal M, Rousaud F, Abian J, Zorzano A, Palacín M, Chillarón J (2002) rBAT-b(0,+)AT heterodimer is the main apical reabsorption system for cystine in the kidney. Am J Physiol 283:F540–F548

    Google Scholar 

  20. Furriols M, Chillarón J, Mora C, Castelló A, Bertran J, Camps M, Testar X, Vilaró S, Zorzano A, Palacín M (1993) rBAT, related tol-cysteine transport, is localized to the microvilli of proximal straight tubules, and its expression is regulated in kidney by development. J Biol Chem 268:27060–27068

    CAS  PubMed  Google Scholar 

  21. Hemler ME, Strominger JL (1982) Characterization of antigen recognized by the monoclonal antibody (4F2): different molecular forms on human T and B lymphoblastoid cell lines. J Immunol 129:623–628

    CAS  PubMed  Google Scholar 

  22. International Cystinuria Consortium (Feliubadalo L, Font M, Purroy J, Rousaud F, Estivill X, Nunes V, Golomb E, Centola M, Aksentijevich I, Kreiss Y, Goldman B, Pras M, Kastner DL, Pras E, Gasparini P, Bisceglia L, Beccia E, Gallucci M, Sanctis L de, Ponzone A, Rizzoni GF, Zelante L, Bassi MT, George AL Jr, Palacín M, et al) (1999) Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b0,+AT) of rBAT. Nat Genet 23:52–57

    CAS  PubMed  Google Scholar 

  23. Janecek S, Svensson B, Henrissat B (1997) Domain evolution in the alpha-amylase family. J Mol Evol 45:322–331

    CAS  PubMed  Google Scholar 

  24. Lee WS, Wells RG, Sabbag RV, Mohandas TK, Hediger MA (1993) Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic, and neutral amino acid transport. J Clin Invest 91:1959–1963

    CAS  PubMed  Google Scholar 

  25. Markovich D, Stange G, Bertran J, Palacín M, Werner A, Biber J, Murer H (1993) Two mRNA transcripts (rBAT-1 and rBAT-2) are involved in system b0,(+)-related amino acid transport. J Biol Chem 268:1362–1367

    CAS  PubMed  Google Scholar 

  26. Matsuo H, Kanai Y, Kim JY, Chairoungdua A, Kim DK, Inatomi J, Shigeta Y, Ishimine H, Chaekuntode S, Tachampa K, Choi HW, Babu E, Fukuda J, Endou H (2002) Identification of a novel Na+-independent acidic amino acid transporter with structural similarity to the member of a heterodimeric amino acid transporter family associated with unknown heavy chains. J Biol Chem 277:21017–21026

    CAS  PubMed  Google Scholar 

  27. Palacín M, Goodyer P, Nunes V, Gasparini P (2001). Cystinuria. In: Scriver CR, Beaudet AL, Sly SW, Valle D (eds) Metabolic and molecular bases of inherited diseases, 8th edn. McGraw-Hill, New York, pp 4909–4932. Revised ONLINE edition (2002) In: genetics.accessmedicine.com. McGraw-Hill, Chapter 191. Cystinuria).

    Google Scholar 

  28. Pfeiffer R, Spindler B, Loffing J, Skelly PJ, Shoemaker CB, Verrey F (1998) Functional heterodimeric amino acid transporters lacking cystine residues involved in disulfide bond. FEBS Lett 439:157–162

    Article  CAS  PubMed  Google Scholar 

  29. Pfeiffer R, Loffing J, Rossier G, Bauch C, Meier C, Eggermann T, Loffing-Cueni D, Kuhn LC, Verrey F (1999) Luminal heterodimeric amino acid transporter defective in cystinuria. Mol Biol Cell 10:4135–4147

    CAS  PubMed  Google Scholar 

  30. Pickel VM, Nirenberg MJ, Chan J, Mosckovitz R, Udenfriend S, Tate SS (1993) Ultrastructural localization of a neutral and basic amino acid transporter in rat kidney and intestine. Proc Natl Acad Sci USA 90:7779–7783

    CAS  PubMed  Google Scholar 

  31. Quackenbush E, Clabby M, Gottesdiener KM, Barbosa J, Jones NH, Strominger JL, Speck S, Leiden JM (1987) Molecular cloning of complementary DNAs encoding the heavy chain of the human 4F2 cell-surface antigen: a type II membrane glycoprotein involved in normal and neoplastic cell growth. Proc Natl Acad Sci USA 84:6526–6530

    CAS  PubMed  Google Scholar 

  32. Reig N, Chillaron J, Bartoccioni P, Fernandez E, Bendahan A, Zorzano A, Kanner B, Palacín M, Bertran J (2002) The light subunit of system b(o,+) is fully functional in the absence of the heavy subunit. EMBO J 21:4906–4914

    Article  CAS  PubMed  Google Scholar 

  33. Shishido T, Uno S, Kamohara M, Tsuneoka-Suzuki T, Hashimoto Y, Enomoto T, Masuko T (2000) Transformation of BALB3T3 cells caused by over-expression of rat CD98 heavy chain (HC) requires its association with light chain: mis-sense mutation in a cysteine residue of CD98HC eliminates its transforming activity. Int J Cancer 87:311–316

    Article  CAS  PubMed  Google Scholar 

  34. Tate SS, Yan N, Udenfriend S (1992) Expression cloning of a Na(+)-independent neutral amino acid transporter from rat kidney. Proc Natl Acad Sci USA 89:1–5

    PubMed  Google Scholar 

  35. Teixeira S, Di Grandi S, Kuhn LC (1987) Primary structure of the human 4F2 antigen heavy chain predicts a transmembrane protein with a cytoplasmic NH2 terminus. J Biol Chem 262:9574–9580

    CAS  PubMed  Google Scholar 

  36. Tsurudome M, Ito Y (2000) Function of fusion regulatory proteins (FRPs) in immune cells and virus-infected cells. Crit Rev Immunol 20:167–196

    CAS  PubMed  Google Scholar 

  37. Van Winkle LJ, Campione AL, Gorman JM (1988) Na+-independent transport of basic and zwitterionic amino acids in mouse blastocysts by a shared system and by processes which distinguish between these substrates. J Biol Chem 263:3150–3163

    PubMed  Google Scholar 

  38. Verrey F, Meier C, Rossier G, Kuhn LC (2000) Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity. Pflugers Arch 440:503–512

    CAS  PubMed  Google Scholar 

  39. Wagner CA, Lang F, Broer S (2001) Function and structure of heterodimeric amino acid transporters. Am J Physiol 281:C1077–C1093

    CAS  Google Scholar 

  40. Watanabe K, Hata Y, Kizaki H, Katsube Y, Suzuki Y (1997) The refined crystal structure of Bacillus cereus oligo-1,6-glucosidase at 2.0 A resolution: structural characterization of proline-substitution sites for protein thermostabilization. J Mol Biol 269:142–153

    Article  CAS  PubMed  Google Scholar 

  41. Wells RG, Hediger MA (1992) Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proc Natl Acad Sci USA 89:5596–5600

    CAS  PubMed  Google Scholar 

  42. Wells RG, Lee WS, Kanai Y, Leiden JM, Hediger MA (1992) The 4F2 antigen heavy chain induces uptake of neutral and dibasic amino acids in Xenopus oocytes. J Biol Chem 267:15285–15288

    CAS  PubMed  Google Scholar 

  43. Yagita H, Masuko T, Hashimoto Y (1986) Inhibition of tumor cell growth in vitro by murine monoclonal antibodies that recognize a proliferation-associated cell surface antigen system in rats and humans. Cancer Res 46:1478–1484

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Robin Rycroft for editing the manuscript. The laboratory of M.P. is supported by the Spanish Dirección General de Investigación Científica y Técnica Research Grant PM 99/0172, the Comissionat per a Universitats i Recerca and Grant 2001SGR00118 from the Generalitat de Catalunya (Spain), and the Instituto de Salud Carlos III network G03/054 (Spain). The laboratory of Y.K. is supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Society for the Promotion of Science, and the Promotion and Mutual Aid Corporation for Private Schools of Japan.

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  1. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Parc Cientìfic de Barcelona, Avda. Diagonal 645, 08028, Barcelona, Spain

    Manuel Palacín

  2. Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611, Tokyo, Japan

    Yoshikatsu Kanai

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Correspondence to Manuel Palacín.

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Palacín, M., Kanai, Y. The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch - Eur J Physiol 447, 490–494 (2004). https://doi.org/10.1007/s00424-003-1062-7

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  • DOI: https://doi.org/10.1007/s00424-003-1062-7

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