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Eukaryotic zinc transporters and their regulation

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Abstract

The last ten years have witnessed major advances in our understanding of zinc transporters and their regulation in eukaryotic organisms. Two families of transporters, the ZIP (Zrt-, Irt-like Protein) and CDF (Cation Diffusion Facilitator) families, have been found to play a number of important roles in zinc transport. These are ancient gene families that span all phylogenetic levels. The characterized members of each group have been implicated in the transport of metal ions, frequently zinc, across lipid bilayer membranes. This remarkable conservation of function suggests that other, as yet uncharacterized members of the family, will also be involved in metal ion transport. Many of the ZIP family transporters are involved in cellular zinc uptake and at least one member, the Zrt3 transporter of S. cerevisiae, transports stored zinc out of an intracellular compartment during adaptation to zinc deficiency. In contrast, CDF family members mediate zinc efflux out of cells or facilitate zinc transport into intracellular compartments for detoxification and/or storage. The activity of many of these transporters is regulated in response to zinc through transcriptional and post-transcriptional mechanisms to maintain zinc homeostasis at both the cellular and organismal levels.

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References

  • Altschul S, Madden T, Schaffer A, Zhang J, Zhang Z, Miller W, Lipman D. 1997 Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucl Acids Res 25, 3389-3402.

    Google Scholar 

  • Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. 1990 Basic local alignment search tool. J Mol Biol 215, 403-410.

    Google Scholar 

  • Anton A, Grosse C, Reismann J, Pribyl T, Nies DH. 1999 CzcD is a heavy metal transporter involved in regulation of heavy metal resistance in Ralstonia sp. Strain CH34. J Bacteriol 181, 6876-6881.

    Google Scholar 

  • Bird AJ, Evans-Galea M, Blankman E, Zhao H, Luo H, Winge DR, Eide DJ. 2000a Mapping the DNA binding domain of the Zap1 zinc-responsive transcriptional activator. J Biol Chem 275, 16160-16166.

    Google Scholar 

  • Bird AJ, Zhui H, Luo H, Jensen LT, Srinivasan C, Evans-Galea M, Winge DR, Eide DJ. 2000b A dual role for zinc fingers in both DNA binding and zinc sensing by the Zap1 transcriptional activator. EMBO J 19, 3704-3713.

    Google Scholar 

  • Bode HP, Dumschat M, Garotti S, Fuhrmann GF. 1995 Iron sequestration by the yeast vacuole. Eur J Biochem 228 337-342.

    Google Scholar 

  • Brown SL, Chaney RL, Angle JS, Baker AJM. 1995 Zinc and cadmium uptake by hyperaccumulator Thlaspi caerulescens grown in nutrient solution. Soil Sci Soc Am J 59, 125-132.

    Google Scholar 

  • Cohen CK, Fox TC, Garvin DF, Kochian LV. 1998 The role of irondeficiency stress responses in stimulating heavy-metal transport in plants. Plant Physiol 116, 1063-1072.

    Google Scholar 

  • Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD. 1999 Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci USA 96, 1716-1721.

    Google Scholar 

  • Conklin DS, Culbertson MR, Kung C. 1994 Interactions between gene products involved in divalent cation transport in Saccharomyces cerevisiae. Mol Gen Genet 244, 303-311.

    Google Scholar 

  • Conklin DS, McMaster JA, Culbertson MR, Kung C. 1992 COT1, a gene involved in cobalt accumulation in Saccharomyces cerevisiae. Mol Cell Biol 12, 3678-3688.

    Google Scholar 

  • Costello LC, Liu Y, Zou J, Franklin RB. 1999 Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone. J Biol Chem 274, 17499-17504.

    Google Scholar 

  • Eide D, Bridgham JT, Zhong Z, Mattoon J. 1993 The vacuolar H+-ATPase of Saccharomyces cerevisiae is required for effi-cient copper detoxification, mitochondrial function, and iron metabolism. Mol Gen Genet 241, 447-456.

    Google Scholar 

  • Eide D, Broderius M, Fett J, Guerinot ML. 1996 A novel ironregulated metal transporter from plants identified by functional expression in yeast. Proc Natl Acad Sci USA 93, 5624-5628.

    Google Scholar 

  • Eng BH, Guerinot ML, Eide D, Saier MH. 1998 Sequence analyses and phylogenetic characterization of the ZIP family of metal ion transport proteins. J Membr Biol 166, 1-7.

    Google Scholar 

  • Fredrickson CJ, Suh SW, Silva D, Fredrickson CJ, Thompson RB. 2000 Importance of zinc in the central nervous system: the zinccontaining neuron. J Nutr 130, 1471S-1483S.

    Google Scholar 

  • Fuhrmann GF, Rothstein A. 1968 The transport of Zn2+, Co2+ and Ni2+ into yeast cells. Biochim Biophys Acta 163, 325-330.

    Google Scholar 

  • Gaither LA, Eider DJ. 2001 The human ZIP1 transporter mediates zinc uptake in human K56Z erythroleukemia cells. J Biol Chem 276, 22258-22264.

    Google Scholar 

  • Gaither LA, Eide DJ. 2000 Functional characterization of the human hZIP2 zinc transporter. J Biol Chem 275, 5560-5564.

    Google Scholar 

  • Gitan RS, Eide DJ. 2000 Zinc-regulated ubiquitin conjugation signals endocytosis of the yeast ZRT1 zinc transporter. Biochem J 346, 329-336.

    Google Scholar 

  • Gitan RS, Lou H, Rodgers J, Broderius M, Eide D. 1998 Zincinduced inactivation of the yeast ZRT1 zinc transporter occurs through endocytosis and vacuolar degradation. J Biol Chem 273, 28617-28624.

    Google Scholar 

  • Grotz N, Fox T, Connolly E, Park W, Guerinot ML, Eide D. 1998 Identification of a family of zinc transporter genes from Arabidopsis that respond to zinc deficiency. Proc Natl Acad Sci USA 95, 7220-7224.

    Google Scholar 

  • Guerinot ML. 2000 The ZIP family of metal transporters. Biochim Biophys Acta 1465, 190-198.

    Google Scholar 

  • Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA. 1997 Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482-488.

    Google Scholar 

  • Hamer DH. 1986 Metallothionein. Annu Rev Biochem 55, 913-951.

    Google Scholar 

  • Hicke L. 1997 Ubiquitin-dependent internalization and downregulation of plasma membrane proteins. FASEB J 11, 1215-1226.

    Google Scholar 

  • Huang L, Gitschier J. 1997 A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nature Genet 17, 292-297.

    Google Scholar 

  • Kamizono A, Nishizawa M, Teranishi Y, Murata K, Kimura A. 1989 Identification of a gene conferring resistance to zinc and cadmium ions in the yeast Saccharomyces cerevisiae. Mol Gen Genet 219, 161-167.

    Google Scholar 

  • Kobayashi S, Miyabe S, Izawa S, Inoue Y, Kimura A. 1996 Correlation of the OSR1/ZRC1 gene product and the intracellular glutathione levels in Saccharomyces cerevisiae. Biotech Appl Biochem 23, 3-6.

    Google Scholar 

  • Kobayashi T, Beuchat M, Lindsay M, Frias S, Palmiter RD, Sakuraba H, Parton RG, Gruenberg J. 1999 Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nature Cell Biol 1, 113-118.

    Google Scholar 

  • Koh J, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW. 1996 The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272, 1013-1016.

    Google Scholar 

  • Korshunova YO, Eide D, Clark WG, Guerinot ML, Pakrasi HB. 1999 The IRT1 protein from Arabidopsis thaliana is a metal transporter with a broad substrate range. Plant Mol Biol 40, 37-44.

    Google Scholar 

  • Langmade SJ, Ravindra R, Daniels PJ, Andrews GK. 2000 The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene. J Biol Chem 275, 34803-34809.

    Google Scholar 

  • Lasat MM, Pence NS, Garvin DF, Ebbs SD, Kochian LV. 2000 Molecular physiology of zinc transport in the Zn hyperaccumulator Thlaspi caerulescens. J Exp Biol 51, 71-79.

    Google Scholar 

  • Li L, Kaplan J. 1998 Defects in the yeast high affinity iron transport system result in increased metal sensitivity because of the in-creased expression of transporters with a broad transition metal specificity. J Biol Chem 273, 22181-22187.

    Google Scholar 

  • Li L, Kaplan J. 2000 The yeast gene MSC2, a member of the cation diffusion facilitator family, affects the cellular distribution of zinc. J Biol Chem 275, 5036-5043.

    Google Scholar 

  • Lioumi M, Ferguson CA, Sharpe PT, Freeman T, Marenholz I, Mischke D, Heizmann C, Ragoussis J. 1999 Isolation and characterization of human and mouse ZIRTL, a member of the IRT1 family of transporters, mapping within the epidermal differentiation complex. Genomics 62, 272-280.

    Google Scholar 

  • Liuzzi JP, Blanchard RK, Cousins RJ. 2001 Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats. J Nutr 131, 46-52.

    Google Scholar 

  • MacDiarmid CW, Gaither LA, Eide D. 2000 Zinc transporters that regulate vacuolar zinc storage in Saccharomyces cerevisiae. EMBO J 19, 2845-2855.

    Google Scholar 

  • Magneson GR, Puvathingal JM, Ray WJ. 1987 The concentrations of free Mg2+ and Zn2+ in equine blood plasma. J Biol Chem 262, 11140-11148.

    Google Scholar 

  • Manning DL, McClelland RA, Knowlden JM, Bryant S, Gee JM, Green CD, Robertson JF, Blamey RW, Sutherland RL, Ormandy CJ, Nicholson RI. 1995 Differential expression of oestrogen regulated genes in breast cancer. Acta Oncol 34, 641-646.

    Google Scholar 

  • McClung JP, Bobilya DJ. 1999 The influence of zinc status on the kinetics of zinc uptake into cultured endothelial cells. J Nutr Biochem 10, 484-489.

    Google Scholar 

  • McGowan SJ, Gorham HC, Hodgson DA. 1993 Light-induced carotenogenesis in Myxococcus xanthus: DNA sequence analysis of the carR region. Mol Microbiol 10, 713-735.

    Google Scholar 

  • McMahon RJ, Cousins RJ. 1998a Mammalian zinc transporters. J Nutr 128, 667-670.

    Google Scholar 

  • McMahon RJ, Cousins RJ. 1998b Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc Natl Acad Sci USA 95, 4841-4846.

    Google Scholar 

  • Menard MP, Cousins RJ. 1983 Zinc transport by brush border membrane vesicles from rat intestine. J Nutr 113, 1434-1442.

    Google Scholar 

  • Mowll JL, Gadd GM. 1983 Zinc uptake and toxicity in the yeast Sporobolomyces roseus and Saccharomyces cerevisiae. J Gen Microbiol 129, 3421-3425.

    Google Scholar 

  • Murgia C, Vespignani I, Cerase J, Nobili F, Perozzi G. 1999 Cloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4 in intestinal tissue and cells. Am J Physiol 277, G1231-G1239.

    Google Scholar 

  • Nies DH, Silver S. 1995 Ion efflux systems involved in bacterial metal resistances. J Ind Microbiol 14, 186-199.

    Google Scholar 

  • Nishimura K, Igarashi K, Kakinuma Y. 1998 Proton gradient-driven nickel uptake by vacuolar membrane vesicles of Saccharomyces cerevisiae. J Bacteriol 180, 1962-1964.

    Google Scholar 

  • Palmiter RD, Cole TB, Findley SD. 1996a ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J 15, 1784-1791.

    Google Scholar 

  • Palmiter RD, Cole TB, Quaife CJ, Findley SD. 1996b ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci USA 93, 14934-14939.

    Google Scholar 

  • Palmiter RD, Findley SD. 1995 Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 14, 639-649.

    Google Scholar 

  • Patzer SI, Hantke K. 1998 The ZnuABC high affinity zinc uptake system and its regulator Zur in Escherichia coli. Mol Microbiol 28, 1199-1210.

    Google Scholar 

  • Paulsen IT, Saier MH. 1997 A novel family of ubiquitous heavy metal ion transport proteins. J Membr Biol 156, 99-103.

    Google Scholar 

  • Pence NS, Larsen PB, Ebbs SD, Letham DL, Lasat MM, Garvin DF, Eide D, Kochian LV. 2000 The molecular physiology of heavy metal transport in the Zn/Cd hyperaccumulator Thlaspi caerulescens. Proc Natl Acad Sci USA 97, 4956-4960.

    Google Scholar 

  • Piletz JE, Ganschow RE. 1978 Zinc deficiency in murine milk underlies expression of the lethal milk (lm) mutation. Science 199, 181-183.

    Google Scholar 

  • Ramsay LM, Gadd GM. 1997 Mutants of Saccharomyces cerevisiae defective in vacuolar function confirm a role for the vacuole in toxic metal ion detoxification. FEMS Microbiol Lett 152, 293-298.

    Google Scholar 

  • Raskin I. 1995 Plant genetic engineering may help with environmental cleanup. Proc Natl Acad Sci USA 93, 3164-3166.

    Google Scholar 

  • Rensing CBM, Rosen BP. 1997 The zntA gene of Escherichia coli encodes a Zn(II)-translocating P-type ATPase. Proc Natl Acad Sci USA 94, 14326-14331.

    Google Scholar 

  • Reyes JG. 1996 Zinc transport in mammalian cells. Am J Physiol 270, C401-C410.

    Google Scholar 

  • Rhodes D, Klug A. 1993 Zinc fingers. Sci Am 268, 56-65.

    Google Scholar 

  • Rogers EE, Eide DJ, Guerinot ML. 2000 Altered selectivity in an Arabidopsis metal transporter. Proc Natl Acad Sci USA 97, 12356-12360.

    Google Scholar 

  • Sacher A, Cohen A, Nelson N. 2001 Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. J Exp Biol 204, 1053-1061.

    Google Scholar 

  • Stein WD. 1990 Channels, Carriers, and Pumps: An Introduction to Membrane Transport. Academic Press, San Diego; pp. 35-38.

    Google Scholar 

  • Suhy D, O'Halloran TV. 1995 Metal responsive gene regulation and the zinc metalloregulatory model. In: Sigel H, ed. Metal Ions in Biological Systems. Marcel Dekker, New York; Vol. 32, pp. 557-578.

    Google Scholar 

  • Sytkowski AJ. 1977 Metal stoichiometry, coenzyme binding, and zinc and cobalt exchange in highly purified yeast alcohol dehydrogenase. Arch Biochem Biophys 184, 505-517.

    Google Scholar 

  • Taylor KM. 2000 LIV-1 breast cancer protein belongs to a new family of histidine-rich membrane proteins with potential to control intracellular zinc homeostasis. Life 49, 249-253.

    Google Scholar 

  • Thompson DA, Stahl FW. 1999 Genetic control of recombination partner preference in yeast meiosis: isolation and characterization of mutants elevated for meiotic unequal sister-chromatid recombination. Genetics 153, 621-641.

    Google Scholar 

  • Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG. 1997 The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nuclc Acids Res 25, 4876-4882.

    Google Scholar 

  • Tsuda M, Imaizumi K, Katayama T, Kitagawa K, Wanaka A, Tohyama M, Takagi T. 1997 Expression of zinc transporter gene ZnT-1 is induced after transient ischemia in the gerbil. J Neurosci 17, 6678-6684.

    Google Scholar 

  • Vallee BL, Auld DS. 1990 Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29, 5647-5659.

    Google Scholar 

  • van der Zaal BJ, Neuteboom LW, Pinas JE, Chardonnens AN, Schat H, Verkleij JAC, Hooykaas PJJ. 1999 Overexpression of a novel Arabidopsis gene related to putative zinc-transporter genes from animals can lead to enhanced zinc resistance and accumulation. Plant Physiol 119, 1047-1055.

    Google Scholar 

  • Victery W, Smith JM, Vander AJ. 1981 Renal tubular handling of zinc in the dog. Am J Physiol 241, F532-F539.

    Google Scholar 

  • Welch RM, Norvell WA, Schaefer SC, Shaff JE, Kochian LV. 1993 Induction of iron(III) and copper(II) reduction in pea (Pisum sativum L.) roots by Fe and Cu status: does the root-cell plasmalemma Fe(III)-chelate reductase perform a general role in regulating cation uptake? Planta 190, 555-561.

    Google Scholar 

  • White C, Gadd GM. 1987 The uptake and cellular distribution of zinc in Saccharomyces cerevisiae. J Gen Microbiol 133, 727-737.

    Google Scholar 

  • Zhang P, Allen JC. 1995 A novel dialysis procedure measuring free Zn2+ in bovine milk and plasma. J Nutr 125, 1904-1910.

    Google Scholar 

  • Zhao H, Butler E, Rodgers J, Spizzo T, Duesterhoeft S. 1998 Regulation of zinc homeostasis in yeast by binding of the ZAP1 transcriptional activator to zinc-responsive promoter elements. J Biol Chem 273, 28713-28720.

    Google Scholar 

  • Zhao H, Eide D. 1996a The yeast ZRT1 gene encodes the zinc transporter of a high affinity uptake system induced by zinc limitation. Proc Natl Acad Sci USA 93, 2454-2458.

    Google Scholar 

  • Zhao H, Eide D. 1996b The ZRT2 gene encodes the low affinity zinc transporter in Saccharomyces cerevisiae. J Biol Chem 271, 23203-23210.

    Google Scholar 

  • Zhao H, Eide D. 1997 Zap1p, a metalloregulatory protein involved in zinc responsive transcriptional regulation in Saccharomyces cerevisiae. Mol Cell Biol 17, 5044-5052.

    Google Scholar 

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Gaither, L.A., Eide, D.J. Eukaryotic zinc transporters and their regulation. Biometals 14, 251–270 (2001). https://doi.org/10.1023/A:1012988914300

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