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. 1990 Oct 1;111(4):1383–1392. doi: 10.1083/jcb.111.4.1383

Intracellular interactions of transferrin and its receptor during biosynthesis

PMCID: PMC2116245  PMID: 2211816

Abstract

The interactions between transferrin (Tf) and transferrin receptor (Tfr) as they occur during biosynthesis were studied in the human hepatoma cell line HepG2, which synthesizes both. Early during biosynthesis the Tfr monomer is converted to a disulfide-linked Tfr dimer. The Tfr monomer is not able to bind Tf, but Tf binding is observed as soon as the covalent Tfr dimer is formed and can take place in the ER. The Tf-Tfr complex is transported through the Golgi reticulum and trans-Golgi reticulum (TGR) and is ultimately delivered to an acidic compartment, where Tf releases its Fe3+. We did not observe conversion of Tf to apoTf in the TGR, showing that the part of the TGR passed by secreted Tf has a pH higher than 5.5. We conclude that when a ligand-receptor combination is synthesized by one and the same cell, ligand and receptor can interact during biosynthesis and be transported to the cell surface.

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Selected References

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  1. Alvarez E., Gironès N., Davis R. J. Intermolecular disulfide bonds are not required for the expression of the dimeric state and functional activity of the transferrin receptor. EMBO J. 1989 Aug;8(8):2231–2240. doi: 10.1002/j.1460-2075.1989.tb08347.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson R. G., Pathak R. K. Vesicles and cisternae in the trans Golgi apparatus of human fibroblasts are acidic compartments. Cell. 1985 Mar;40(3):635–643. doi: 10.1016/0092-8674(85)90212-0. [DOI] [PubMed] [Google Scholar]
  3. Berger E. G., Thurnher M., Müller U. Galactosyltransferase and sialyltransferase are located in different subcellular compartments in HeLa cells. Exp Cell Res. 1987 Nov;173(1):267–273. doi: 10.1016/0014-4827(87)90352-1. [DOI] [PubMed] [Google Scholar]
  4. Bischoff J., Libresco S., Shia M. A., Lodish H. F. The H1 and H2 polypeptides associate to form the asialoglycoprotein receptor in human hepatoma cells. J Cell Biol. 1988 Apr;106(4):1067–1074. doi: 10.1083/jcb.106.4.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem. 1987;56:881–914. doi: 10.1146/annurev.bi.56.070187.004313. [DOI] [PubMed] [Google Scholar]
  6. Ciechanover A., Schwartz A. L., Dautry-Varsat A., Lodish H. F. Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents. J Biol Chem. 1983 Aug 25;258(16):9681–9689. [PubMed] [Google Scholar]
  7. Dautry-Varsat A., Ciechanover A., Lodish H. F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2258–2262. doi: 10.1073/pnas.80.8.2258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Di Marco E., Pierce J. H., Fleming T. P., Kraus M. H., Molloy C. J., Aaronson S. A., Di Fiore P. P. Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene. 1989 Jul;4(7):831–838. [PubMed] [Google Scholar]
  9. Dobberstein B., Garoff H., Warren G., Robinson P. J. Cell-free synthesis and membrane insertion of mouse H-2Dd histocompatibility antigen and beta 2-microglobulin. Cell. 1979 Aug;17(4):759–769. doi: 10.1016/0092-8674(79)90316-7. [DOI] [PubMed] [Google Scholar]
  10. Drickamer K. Two distinct classes of carbohydrate-recognition domains in animal lectins. J Biol Chem. 1988 Jul 15;263(20):9557–9560. [PubMed] [Google Scholar]
  11. Fuhrmann U., Bause E., Ploegh H. Inhibitors of oligosaccharide processing. Biochim Biophys Acta. 1985 Jun 24;825(2):95–110. doi: 10.1016/0167-4781(85)90095-8. [DOI] [PubMed] [Google Scholar]
  12. Gething M. J., McCammon K., Sambrook J. Expression of wild-type and mutant forms of influenza hemagglutinin: the role of folding in intracellular transport. Cell. 1986 Sep 12;46(6):939–950. doi: 10.1016/0092-8674(86)90076-0. [DOI] [PubMed] [Google Scholar]
  13. Goldstein J. L., Brown M. S., Anderson R. G., Russell D. W., Schneider W. J. Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol. 1985;1:1–39. doi: 10.1146/annurev.cb.01.110185.000245. [DOI] [PubMed] [Google Scholar]
  14. Hopkins C. R. Intracellular routing of transferrin and transferrin receptors in epidermoid carcinoma A431 cells. Cell. 1983 Nov;35(1):321–330. doi: 10.1016/0092-8674(83)90235-0. [DOI] [PubMed] [Google Scholar]
  15. Jing S. Q., Trowbridge I. S. Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid-attachment site. EMBO J. 1987 Feb;6(2):327–331. doi: 10.1002/j.1460-2075.1987.tb04758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Karin M., Mintz B. Receptor-mediated endocytosis of transferrin in developmentally totipotent mouse teratocarcinoma stem cells. J Biol Chem. 1981 Apr 10;256(7):3245–3252. [PubMed] [Google Scholar]
  17. Klausner R. D., Van Renswoude J., Ashwell G., Kempf C., Schechter A. N., Dean A., Bridges K. R. Receptor-mediated endocytosis of transferrin in K562 cells. J Biol Chem. 1983 Apr 25;258(8):4715–4724. [PubMed] [Google Scholar]
  18. Knowles B. B., Howe C. C., Aden D. P. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980 Jul 25;209(4455):497–499. doi: 10.1126/science.6248960. [DOI] [PubMed] [Google Scholar]
  19. Kornfeld S. Trafficking of lysosomal enzymes. FASEB J. 1987 Dec;1(6):462–468. doi: 10.1096/fasebj.1.6.3315809. [DOI] [PubMed] [Google Scholar]
  20. Lozzio C. B., Lozzio B. B. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood. 1975 Mar;45(3):321–334. [PubMed] [Google Scholar]
  21. MacGillivray R. T., Mendez E., Shewale J. G., Sinha S. K., Lineback-Zins J., Brew K. The primary structure of human serum transferrin. The structures of seven cyanogen bromide fragments and the assembly of the complete structure. J Biol Chem. 1983 Mar 25;258(6):3543–3553. [PubMed] [Google Scholar]
  22. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  23. McClelland A., Kühn L. C., Ruddle F. H. The human transferrin receptor gene: genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence. Cell. 1984 Dec;39(2 Pt 1):267–274. doi: 10.1016/0092-8674(84)90004-7. [DOI] [PubMed] [Google Scholar]
  24. Neefjes J. J., Breur-Vriesendorp B. S., van Seventer G. A., Iványi P., Ploegh H. L. An improved biochemical method for the analysis of HLA-class I antigens. Definition of new HLA-class I subtypes. Hum Immunol. 1986 Jun;16(2):169–181. doi: 10.1016/0198-8859(86)90046-7. [DOI] [PubMed] [Google Scholar]
  25. Neefjes J. J., Stollorz V., Peters P. J., Geuze H. J., Ploegh H. L. The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell. 1990 Apr 6;61(1):171–183. doi: 10.1016/0092-8674(90)90224-3. [DOI] [PubMed] [Google Scholar]
  26. Neefjes J. J., Verkerk J. M., Broxterman H. J., van der Marel G. A., van Boom J. H., Ploegh H. L. Recycling glycoproteins do not return to the cis-Golgi. J Cell Biol. 1988 Jul;107(1):79–87. doi: 10.1083/jcb.107.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Omary M. B., Trowbridge I. S. Biosynthesis of the human transferrin receptor in cultured cells. J Biol Chem. 1981 Dec 25;256(24):12888–12892. [PubMed] [Google Scholar]
  28. Reed R. G., Burrington C. M. The albumin receptor effect may be due to a surface-induced conformational change in albumin. J Biol Chem. 1989 Jun 15;264(17):9867–9872. [PubMed] [Google Scholar]
  29. Regoeczi E., Chindemi P. A., Debanne M. T., Charlwood P. A. Partial resialylation of human asialotransferrin type 3 in the rat. Proc Natl Acad Sci U S A. 1982 Apr;79(7):2226–2230. doi: 10.1073/pnas.79.7.2226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Roth J., Taatjes D. J., Lucocq J. M., Weinstein J., Paulson J. C. Demonstration of an extensive trans-tubular network continuous with the Golgi apparatus stack that may function in glycosylation. Cell. 1985 Nov;43(1):287–295. doi: 10.1016/0092-8674(85)90034-0. [DOI] [PubMed] [Google Scholar]
  31. Schneider C., Owen M. J., Banville D., Williams J. G. Primary structure of human transferrin receptor deduced from the mRNA sequence. Nature. 1984 Oct 18;311(5987):675–678. doi: 10.1038/311675b0. [DOI] [PubMed] [Google Scholar]
  32. Schneider C., Sutherland R., Newman R., Greaves M. Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9. J Biol Chem. 1982 Jul 25;257(14):8516–8522. [PubMed] [Google Scholar]
  33. Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  34. Thrift R. N., Forte T. M., Cahoon B. E., Shore V. G. Characterization of lipoproteins produced by the human liver cell line, Hep G2, under defined conditions. J Lipid Res. 1986 Mar;27(3):236–250. [PubMed] [Google Scholar]
  35. Turkewitz A. P., Schwartz A. L., Harrison S. C. A pH-dependent reversible conformational transition of the human transferrin receptor leads to self-association. J Biol Chem. 1988 Nov 5;263(31):16309–16315. [PubMed] [Google Scholar]
  36. Yang F., Lum J. B., McGill J. R., Moore C. M., Naylor S. L., van Bragt P. H., Baldwin W. D., Bowman B. H. Human transferrin: cDNA characterization and chromosomal localization. Proc Natl Acad Sci U S A. 1984 May;81(9):2752–2756. doi: 10.1073/pnas.81.9.2752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. van de Rijn M., Geurts van Kessel A. H., Kroezen V., van Agthoven A. J., Verstijnen K., Terhorst C., Hilgers J. Localization of a gene controlling the expression of the human transferrin receptor to the region q12 leads to qter of chromosome 3. Cytogenet Cell Genet. 1983;36(3):525–531. doi: 10.1159/000131967. [DOI] [PubMed] [Google Scholar]

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