Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter

Journal of Biological Chemistry

Volumn 287, Issue 7, 2012, Pages 4982-4995

  Hou, Zhanjun ^a,e   Desmoulin, Sita Kugel ^b   Etnyre, Erika ^a   Olive, Mary ^c   Hsiung, Benjamin ^a   Cherian, Christina ^a   Wloszczynski, Patrick A ^a   Moin, Kamiar ^c,d   Matherly, Larry H ^a,b,d,e  

^a KARMANOS CANCER INSTITUTE   (United States)

^b Cancer Biology Graduate Program   (United States)

^c Marketing & Education   (United States)

^d WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e NONE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL MEMBRANES; CHEMOTHERAPY; CROSSLINKING; CYTOLOGY; ELECTROPHORESIS; ENERGY TRANSFER; EPITOPES; FLUORESCENCE; LANTHANUM COMPOUNDS; MONOMERS; TUMORS;

CHEMICAL CROSS-LINKING; FLUORESCENCE RESONANCE ENERGY TRANSFER; INTESTINAL ABSORPTION; MAJOR FACILITATOR SUPERFAMILY; POLYACRYLAMIDE GEL ELECTROPHORESIS; POSITIVE COOPERATIVITY; TARGETED CHEMOTHERAPY; THERAPEUTIC APPLICATION;

DIMERS;

OLIGOMER; PROTON COUPLED FOLATE TRANSPORTER;

ARTICLE; BIOTINYLATION; CELL MEMBRANE; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DEGLYCOSYLATION; DENSITOMETRY; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMAN; HUMAN CELL; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN CROSS LINKING; PROTEIN EXPRESSION; PROTEIN FUNCTION;

EID: 84856912045     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M111.306860     Document Type: Article

References (63)

1. Stokstad, E. L. R. (ed) (1990) Historical Perspective on Key Advances in the Biochemistry and Physiology of Folates, pp. 1-21, Wiley-Liss, New York
2. Zhao, R., Matherly, L. H., and Goldman, I. D. (2009) Membrane transporters and folate homeostasis. Intestinal absorption and transport into systemic compartments and tissues. Expert. Rev. Mol. Med. 11, e4
3. Zhao, R., and Goldman, I. D. (2007) The molecular identity and characterization of a proton-coupled folate transporter - PCFT. Biological ramifications and impact on the activity of pemetrexed. Cancer Metastasis Rev. 26, 129-139 (Pubitemid 46452187)
4. Nakai, Y., Inoue, K., Abe, N., Hatakeyama, M., Ohta, K. Y., Otagiri, M., Hayashi, Y., and Yuasa, H. (2007) Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J. Pharmacol. Exp. Ther. 322, 469-476 (Pubitemid 47105788)
5. Qiu, A., Jansen, M., Sakaris, A., Min, S. H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M. H., and Goldman, I. D. (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917-928 (Pubitemid 44792250)
6. Zhao, R., Min, S. H., Qiu, A., Sakaris, A., Goldberg, G. L., Sandoval, C., Malatack, J. J., Rosenblatt, D. S., and Goldman, I. D. (2007) The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110, 1147-1152 (Pubitemid 47281410)
7. Min, S. H., Oh, S. Y., Karp, G. I., Poncz, M., Zhao, R., and Goldman, I. D. (2008) The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. J. Pediatr. 153, 435-437
8. Lasry, I., Berman, B., Straussberg, R., Sofer, Y., Bessler, H., Sharkia, M., Glaser, F., Jansen, G., Drori, S., and Assaraf, Y. G. (2008) A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg-113 is crucial for function. Blood 112, 2055-2061
9. Borzutzky, A., Crompton, B., Bergmann, A. K., Giliani, S., Baxi, S., Martin, M., Neufeld, E. J., and Notarangelo, L. D. (2009) Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clin. Immunol. 133, 287-294
10. Meyer, E., Kurian, M. A., Pasha, S., Trembath, R. C., Cole, T., and Maher, E. R. (2010) A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption. Mol. Genet. Metab. 99, 325-328
11. Atabay, B., Turker, M., Ozer, E. A., Mahadeo, K., Diop-Bove, N., and Goldman, I. D. (2010) Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. Pediatr. Hematol. Oncol. 27, 614-619
12. Mahadeo, K., Diop-Bove, N., Shin, D., Unal, E. S., Teo, J., Zhao, R., Chang, M. H., Fulterer, A., Romero, M. F., and Goldman, I. D. (2010) Properties of the Arg-376 residue of the proton-coupled folate transporter (PCFTSLC46A1) and a glutamine mutant causing hereditary folate malabsorption. Am. J. Physiol. Cell Physiol. 299, C1153-C1161
13. Shin, D. S., Min, S. H., Russell, L., Zhao, R., Fiser, A., and Goldman, I. D. (2010) Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1). A D156Y mutation causing hereditary folate malabsorption. Blood 116, 5162-5169
14. Mahadeo, K. M., Diop-Bove, N., Ramirez, S. I., Cadilla, C. L., Rivera, E., Martin, M., Lerner, N. B., DiAntonio, L., Duva, S., Santiago-Borrero, P. J., and Goldman, I. D. (2011) Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico. J. Pediatr. 159, 623-627
15. Shin, D. S., Mahadeo, K., Min, S. H., Diop-Bove, N., Clayton, P., Zhao, R., and Goldman, I. D. (2011) Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Mol. Genet. Metab. 103, 33-37
16. Zhao, R., Qiu, A., Tsai, E., Jansen, M., Akabas, M. H., and Goldman, I. D. (2008) The proton-coupled folate transporter. Impact on pemetrexed transport and on antifolate activities compared with the reduced folate carrier. Mol. Pharmacol. 74, 854-862
17. Vogelzang, N. J., Rusthoven, J. J., Symanowski, J., Denham, C., Kaukel, E., Ruffie, P., Gatzemeier, U., Boyer, M., Emri, S., Manegold, C., Niyikiza, C., and Paoletti, P. (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 21, 2636-2644 (Pubitemid 46606305)
18. Hanna, N., Shepherd, F. A., Fossella, F. V., Pereira, J. R., De Marinis, F., von Pawel, J., Gatzemeier, U., Tsao, T. C., Pless, M., Muller, T., Lim, H. L., Desch, C., Szondy, K., Gervais, R., Shaharyar, Manegold, C., Paul, S., Paoletti, P., Einhorn, L., and Bunn, P. A., Jr. (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J. Clin. Oncol. 22, 1589-1597 (Pubitemid 41079796)
19. Ciuleanu, T., Brodowicz, T., Zielinski, C., Kim, J. H., Krzakowski, M., Laack, E., Wu, Y. L., Bover, I., Begbie, S., Tzekova, V., Cucevic, B., Pereira, J. R., Yang, S. H., Madhavan, J., Sugarman, K. P., Peterson, P., John, W. J., Krejcy, K., and Belani, C. P. (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer. A randomized, double-blind, phase 3 study. Lancet 374, 1432-1440
20. Zhao, R., Gao, F., Hanscom, M., and Goldman, I. D. (2004) A prominent low-pH methotrexate transport activity in human solid tumors. Contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier. Clin. Cancer Res. 10, 718-727 (Pubitemid 38180440)
21. Kugel Desmoulin, S., Wang, L., Hales, E., Polin, L., White, K., Kushner, J., Stout, M., Hou, Z., Cherian, C., Gangjee, A., and Matherly, L. H. (2011) Therapeutic targeting of a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate to human solid tumors based on selective uptake by the proton-coupled folate transporter. Mol. Pharmacol. 80, 1096-1107
22. Helmlinger, G., Yuan, F., Dellian, M., and Jain, R. K. (1997) Interstitial pH and pO2 gradients in solid tumors in vivo. High-resolution measurements reveal a lack of correlation. Nat. Med. 3, 177-182 (Pubitemid 27064702)
23. Raghunand, N., Altbach, M. I., van Sluis, R., Baggett, B., Taylor, C. W., Bhujwalla, Z. M., and Gillies, R. J. (1999) Plasmalemmal pH gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy. Biochem. Pharmacol. 57, 309-312 (Pubitemid 29056209)
24. Desmoulin, S. K., Wang, Y., Wu, J., Stout, M., Hou, Z., Fulterer, A., Chang, M. H., Romero, M. F., Cherian, C., Gangjee, A., and Matherly, L. H. (2010) Targeting the proton-coupled folate transporter for selective delivery of 6-substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of de novo purine biosynthesis in the chemotherapy of solid tumors. Mol. Pharmacol. 78, 577-587
25. Wang, L., Cherian, C., Desmoulin, S. K., Polin, L., Deng, Y., Wu, J., Hou, Z., White, K., Kushner, J., Matherly, L. H., and Gangjee, A. (2010) Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate trans-porter over the reduced folate carrier for cellular entry. J. Med. Chem. 53, 1306-1318
26. Wang, L., Desmoulin, S. K., Cherian, C., Polin, L., White, K., Kushner, J., Fulterer, A., Chang, M. H., Mitchell-Ryan, S., Stout, M., Romero, M. F., Hou, Z., Matherly, L. H., and Gangjee, A. (2011) Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase. J. Med. Chem. 54, 7150-7164
27. Zhao, R., Unal, E. S., Shin, D. S., and Goldman, I. D. (2010) Membrane topological analysis of the proton-coupled folate transporter (PCFTSLC46A1) by the substituted cysteine accessibility method. Biochemistry 49, 2925-2931
28. Unal, E. S., Zhao, R., Qiu, A., and Goldman, I. D. (2008) N-Linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT). Biochim. Biophys. Acta 1778, 1407-1414
29. Qiu, A., Min, S. H., Jansen, M., Malhotra, U., Tsai, E., Cabelof, D. C., Matherly, L. H., Zhao, R., Akabas, M. H., and Goldman, I. D. (2007) Rodent intestinal folate transporters (SLC46A1). Secondary structure, functional properties, and response to dietary folate restriction. Am. J. Physiol. Cell Physiol. 293, C1669-C1678 (Pubitemid 350085626)
30. Unal, E. S., Zhao, R., and Goldman, I. D. (2009) Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1. Am. J. Physiol. Cell Physiol. 297, C66-C74
31. Unal, E. S., Zhao, R., Chang, M. H., Fiser, A., Romero, M. F., and Goldman, I. D. (2009) The functional roles of the His-247 and His-281 residues in folate and proton translocation mediated by the human proton-coupled folate transporter SLC46A1. J. Biol. Chem. 284, 17846-17857
32. Lasry, I., Berman, B., Glaser, F., Jansen, G., and Assaraf, Y. G. (2009) Hereditary folate malabsorption. A positively charged amino acid at position 113 of the proton-coupled folate transporter (PCFT/SLC46A1) is required for folic acid binding. Biochem. Biophys. Res. Commun. 386, 426-431
33. Subramanian, V. S., Marchant, J. S., and Said, H. M. (2008) Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia. Am. J. Physiol. Cell Physiol. 294, C233-C240
34. Veenhoff, L. M., Heuberger, E. H., and Poolman, B. (2001) The lactose transport protein is a cooperative dimer with two sugar translocation pathways. EMBO J. 20, 3056-3062 (Pubitemid 32611993)
35. - transport can be rescued by carbonic anhydrase II presented on an adjacent AE1 protomer. J. Biol. Chem. 278, 44949-44958
36. Taylor, A. M., Zhu, Q., and Casey, J. R. (2001) Cysteine-directed cross-linking localizes regions of the human erythrocyte anion-exchange protein (AE1) relative to the dimeric interface. Biochem. J. 359, 661-668 (Pubitemid 33063391)
37. Zottola, R. J., Cloherty, E. K., Coderre, P. E., Hansen, A., Hebert, D. N., and Carruthers, A. (1995) Glucose transporter function is controlled by transporter oligomeric structure. A single, intramolecular disulfide promotes GLUT1 tetramerization. Biochemistry 34, 9734-9747
38. Yin, C. C., Aldema-Ramos, M. L., Borges-Walmsley, M. I., Taylor, R. W., Walmsley, A. R., Levy, S. B., and Bullough, P. A. (2000) The quarternary molecular architecture of TetA, a secondary tetracycline transporter from Escherichia coli. Mol. Microbiol. 38, 482-492
39. Hickman, R. K., and Levy, S. B. (1988) Evidence that TET protein functions as a multimer in the inner membrane of Escherichia coli. J. Bacteriol. 170, 1715-1720
40. Hou, Z., and Matherly, L. H. (2009) Oligomeric structure of the human reduced folate carrier. Identification of homo-oligomers and dominant-negative effects on carrier expression and function. J. Biol. Chem. 284, 3285-3293
41. Payton, S. G., Haska, C. L., Flatley, R. M., Ge, Y., and Matherly, L. H. (2007) Effects of 5′-untranslated region diversity on the posttranscriptional regulation of the human reduced folate carrier. Biochim. Biophys. Acta 1769, 131-138 (Pubitemid 46341446)
42. Fleming, J. C., Tartaglini, E., Steinkamp, M. P., Schorderet, D. F., Cohen, N., and Neufeld, E. J. (1999) The gene mutated in thiamine-responsive anemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat. Genet. 22, 305-308 (Pubitemid 29297261)
43. Ohashi, T., Galiacy, S. D., Briscoe, G., and Erickson, H. P. (2007) An experimental study of GFP-based FRET, with application to intrinsically unstructured proteins. Protein Sci. 16, 1429-1438 (Pubitemid 46984877)
44. Zacharias, D. A., Violin, J. D., Newton, A. C., and Tsien, R. Y. (2002) Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296, 913-916 (Pubitemid 34464897)
45. Hou, Z., Stapels, S. E., Haska, C. L., and Matherly, L. H. (2005) Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods. J. Biol. Chem. 280, 36206-36213 (Pubitemid 41633893)
46. Matherly, L. H., Czajkowski, C. A., and Angeles, S. M. (1991) Identification of a highly glycosylated methotrexate membrane carrier in K562 human erythroleukemia cells up-regulated for tetrahydrofolate cofactor and methotrexate transport. Cancer Res. 51, 3420-3426
47. Laemmli, U. K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685
48. Wouters, F. S., Verveer, P. J., and Bastiaens, P. I. (2001) Imaging biochemistry inside cells. Trends Cell Biol. 11, 203-211 (Pubitemid 32367877)
49. Witt, T. L., Stapels, S. E., and Matherly, L. H. (2004) Restoration of transport activity by co-expression of human reduced folate carrier half-molecules in transport-impaired K562 cells. Localization of a substrate binding domain to transmembrane domains 7-12. J. Biol. Chem. 279, 46755-46763 (Pubitemid 39518324)
50. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265-275
51. Bamber, L., Harding, M., Monné, M., Slotboom, D. J., and Kunji, E. R. (2007) The yeast mitochondrial ADP/ATP carrier functions as a monomer in mitochondrial membranes. Proc. Natl. Acad. Sci. U.S.A. 104, 10830-10834 (Pubitemid 47175186)
52. MacKinnon, R. (1991) Determination of the subunit stoichiometry of a voltage-activated potassium channel. Nature 350, 232-235
53. Yerushalmi, H., Lebendiker, M., and Schuldiner, S. (1996) Negative dominance studies demonstrate the oligomeric structure of EmrE, a multidrug antiporter from Escherichia coli. J. Biol. Chem. 271, 31044-31048 (Pubitemid 26408541)
54. Hou, Z., Cherian, C., Drews, J., Wu, J., and Matherly, L. H. (2010) Identification of the minimal functional unit of the homo-oligomeric human reduced folate carrier. J. Biol. Chem. 285, 4732-4740
55. Bisetto, E., Giorgio, V., Di Pancrazio, F., Mavelli, I., and Lippe, G. (2007) Characterization of oligomeric forms from mammalian F0F1-ATP synthase by BN-PAGE. The role of detergents. Ital. J. Biochem. 56, 254-258
56. Swamy, M., Siegers, G. M., Minguet, S., Wollscheid, B., and Schamel, W. W. (2006) Blue native polyacrylamide gel electrophoresis (BN-PAGE) for the identification and analysis of multiprotein complexes. Sci. STKE 2006, pl4
57. Heuberger, E. H., Veenhoff, L. M., Duurkens, R. H., Friesen, R. H., and Poolman, B. (2002) Oligomeric state of membrane transport proteins analyzed with blue native electrophoresis and analytical ultracentrifugation. J. Mol. Biol. 317, 591-600 (Pubitemid 34722171)
58. Tsien, R. Y. (1998) The green fluorescent protein. Annu. Rev. Biochem. 67, 509-544
59. Shaner, N. C., Steinbach, P. A., and Tsien, R. Y. (2005) A guide to choosing fluorescent proteins. Nat. Methods 2, 905-909 (Pubitemid 43108726)
60. Abramson, J., Smirnova, I., Kasho, V., Verner, G., Kaback, H. R., and Iwata, S. (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301, 610-615 (Pubitemid 36927939)
61. Polgar, O., Ierano, C., Tamaki, A., Stanley, B., Ward, Y., Xia, D., Tarasova, N., Robey, R. W., and Bates, S. E. (2010) Mutational analysis of threonine 402 adjacent to the GXXXG dimerization motif in transmembrane segment 1 of ABCG2. Biochemistry 49, 2235-2245
62. Duan, P., Wu, J., and You, G. (2011) Mutational analysis of the role of GXXXG motif in the function of human organic anion transporter 1 (hOAT1). Int. J. Biochem. Mol. Biol. 2, 1-7
63. Matherly, L. H., Hou, Z., and Deng, Y. (2007) Human reduced folate carrier. Translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev. 26, 111-128 (Pubitemid 46452186)