2.A.5 The Zinc (Zn2+)-Iron (Fe2+) Permease (ZIP) Family

Most members of the ZIP family consist of 220-650 amino acyl residues with eight putative transmembrane spanners. However, LIV1 of man has been reported to have only 6 TMSs, although it exhibits 8 hydrophobic peaks, and the IAA-alanine resistance protein 1 (Iar1 of A. thaliana) also exhibits 8 TMSs (Lasswell et al., 2000). They are derived from animals, plants, yeast, bacteria and archaea. They comprise a diverse family, with several paralogues in any one organism (e.g., 14 in mammals, at least 5 in Caenorhabditis elegans and Arabidopsis thaliana, 9 in maize and two in Saccharomyces cervisiae). Zinc homeostasis in plants has been reviewed (Ricachenevsky et al. 2015).

The various mammalian paralogues fall into four subfamilies and are found in a variety of cell types, cell locations and tissues, and some are responsive to hormones and cytokines (Dempski 2012). Some mammalian Zip genes apparently do not  play critical roles in zinc homeostasis when zinc is replete, but they play important, noncompensatory roles when this metal is deficient (Kambe et al. 2008).  Zip6 (LIV1) is estrogen responsive in breast cancer cells and is related to metastasis in lymph nodes. Zip8 (Big M103) is TNFα and endotoxin induced in monocytes. The two S. cerevisiae proteins, Zrt1 and Zrt2, both probably transport Zn2+ with high specificity, but Zrt1 transports Zn2+ with ten-fold higher affinity than Zrt2.

Some members of the ZIP family have been shown to transport Zn2+ while others transport Fe2+, and a few have been shown to transport a range of metal ions. One human protein member of the ZIP family is designated ''growth arrest inducible gene product,'' but its presumed transport activity has not been identified. A second human protein, Zip4, is a Zn2+ uptake permease and a disease protein (Cousins et al., 2006). Histidine-rich repeats are found in extracellular N- and C-termini as well as a long intracellular loop, and Zip14 has an extra extracellular his-rich loop. One family of mammalian Zip proteins (the LZT family) has a metaprotease motif (HEXPHEXGD) that may allow them to function as matrix metaloproteases. Zip10 has C2H2 zinc finger and cytochrome c motifs in its first TMS (Cousins et al., 2006).

The energy source for transport has not been characterized, but these systems probably function as secondary carriers. They do not require ATP (Cousins et al., 2006). In one study, uptake of Zn2+ via the hZip2 permease was energy independent, independent of Na+ and K+ gradients, but stimulated by HCO3- (Gaither and Eide, 2000). The authors propose a Zn2+:HCO3- symport mechanism. hZip1 is the major Zn2+ uptake system in many human tissues (Gaither and Eide, 2001). The N-terminal regions are novel substrate selectors in the ZIP family of transporters (Nishida et al., 2011).

Mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth, and connective tissues, reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS), of some features of osteogenesis imperfecta and Zn deficient disorders. The Zip13 knockout (Zip13-KO) mice show defects in the function of osteoblasts, chondrocytes, odontoblasts and fibroblasts. Zip13 protein is localized to the Golgi in the corresponding cells. Impairment in BMP and TGF-beta signaling were observed in Zip13-KO cells (Fukada et al., 2008).  ZIP5, ZIP6, ZIP7, and ZIP10 in rat liver are regulated by iron. They may play a role in hepatic iron/metal homeostasis during iron deficiency and overload (Nam and Knutson, 2012).  In maize, IRT1 is induced by zinc and iron deficiency, ZIP4 is induced during early embryogeneis, ZIP5 is induced during middle embryogeneis, and IRT1 and ZIP6 are induced during late embryogenesis (Li et al. 2013). 

12 members of the Zn/Fe-regulated transporters (ZRT/IRT) (ZIP Family) have been identified and isolated from Poncirus trifoliata, and they were named PtZIPs according to the sequence and functional similarity to Arabidopsis thaliana ZIPs (Fu et al. 2017). The 12 PtZIPs are of 334-419 aas, harboring 6-9 putative TMSs. All contain the conserved ZIP signature sequences in TMS4, and nine of them showed a variable region rich in histidine residues between TMS3 and TMS4.  PtZIPs fall into four phylogenetic groups as for ZIPs of A. thaliana. Expression analyses showed that PtZIP genes are differently induced in roots and leaves under conditions of Zn2+, Fe2+ and Mn2+ deficiency. PtIRT1, PtZIP1, PtZIP2, PtZIP3, and PtZIP12  complement a zrt1 zrt2 mutant, which was deficient in Zn2+ uptake; PtIRT1 and PtZIP7 complement a fet3 fet4 mutant, deficient in Fe2+ uptake, and PtIRT1 complements a smf1 mutant, deficient in Mn2+ uptake, suggesting their respective functions in Zn2+, Fe2+, and Mn2+ transport (Fu et al. 2017).

The generalized transport reaction for members of the ZIP family is:

Me2+ (out) (pmf) → Me2+ (in)



This family belongs to the .

 

References:

Antala S., Ovchinnikov S., Kamisetty H., Baker D. and Dempski RE. (2015). Computation and Functional Studies Provide a Model for the Structure of the Zinc Transporter hZIP4. J Biol Chem. 290(29):17796-805.

Bafaro EM., Antala S., Nguyen TV., Dzul SP., Doyon B., Stemmler TL. and Dempski RE. (2015). The large intracellular loop of hZIP4 is an intrinsically disordered zinc binding domain. Metallomics. 7(9):1319-30.

Berg AH., Rice CD., Rahman MS., Dong J. and Thomas P. (2014). Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: I. Discovery in female atlantic croaker and evidence ZIP9 mediates testosterone-induced apoptosis of ovarian follicle cells. Endocrinology. 155(11):4237-49.

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Cousins, R.J., J.P. Liuzzi, and L.A. Lichten. (2006). Mammalian zinc transport, trafficking, and signals. J. Biol. Chem. 281: 24085-24089.

Dechen, K., C.D. Richards, J.C. Lye, J.E. Hwang, and R. Burke. (2015). Compartmentalized zinc deficiency and toxicities caused by ZnT and Zip gene over expression result in specific phenotypes in Drosophila. Int J Biochem. Cell Biol. 60: 23-33.

Dempski, R.E. (2012). The Cation Selectivity of the ZIP Transporters. Curr Top Membr 69: 221-245.

Diallinas, G. (2017). Transceptors as a functional link of transporters and receptors. Microb Cell 4: 69-73.

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Ehsani, S., A. Salehzadeh, H. Huo, W. Reginold, C.L. Pocanschi, H. Ren, H. Wang, K. So, C. Sato, M. Mehrabian, R. Strome, W.S. Trimble, L.N. Hazrati, E. Rogaeva, D. Westaway, G.A. Carlson, and G. Schmitt-Ulms. (2012). LIV-1 ZIP ectodomain shedding in prion-infected mice resembles cellular response to transition metal starvation. J. Mol. Biol. 422: 556-574.

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Fu, X.Z., X. Zhou, F. Xing, L.L. Ling, C.P. Chun, L. Cao, M.G.M. Aarts, and L.Z. Peng. (2017). Genome-Wide Identification, Cloning and Functional Analysis of the Zinc/Iron-Regulated Transporter-Like Protein (ZIP) Gene Family in Trifoliate Orange (Poncirus trifoliata L. Raf.). Front Plant Sci 8: 588.

Fukada, T., N. Civic, T. Furuichi, S. Shimoda, K. Mishima, H. Higashiyama, Y. Idaira, Y. Asada, H. Kitamura, S. Yamasaki, S. Hojyo, M. Nakayama, O. Ohara, H. Koseki, H.G. Dos Santos, L. Bonafe, R. Ha-Vinh, A. Zankl, S. Unger, M.E. Kraenzlin, J.S. Beckmann, I. Saito, C. Rivolta, S. Ikegawa, A. Superti-Furga, and T. Hirano. (2008). The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways. PLoS One 3: e3642.

Gaither, L.A. and D.J. Eide. (2000). Functional expression of the human hZIP2 zinc transporter. J. Biol. Chem. 275: 5560-5564.

Gaither, L.A. and D.J. Eide. (2001). The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J. Biol. Chem. 276: 22258-22264.

Giacconi, R., L. Costarelli, M. Malavolta, M. Cardelli, R. Galeazzi, F. Piacenza, N. Gasparini, A. Basso, E. Mariani, T. Fulop, L. Rink, G. Dedoussis, G. Herbein, J. Jajte, M. Provinciali, F. Busco, and E. Mocchegiani. (2015). Effect of ZIP2 Gln/Arg/Leu (rs2234632) polymorphism on zinc homeostasis and inflammatory response following zinc supplementation. Biofactors. [Epub: Ahead of Print]

Gomes, D.S., C.J. Riger, M.L. Pinto, A.D. Panek, and E.C. Eleutherio. (2005). Evaluation of the role of Ace1 and Yap1 in cadmium absorption using the eukaryotic cell model Saccharomyces cerevisiae. Environ Toxicol Pharmacol 20: 383-389.

Grass, G., S. Franke, N. Taudte, D.H. Nies, L.M. Kucharski, M.E. Maguire, and C. Rensing. (2005). The metal permease ZupT from Escherichia coli is a transporter with a broad substrate spectrum. J. Bacteriol. 187: 1604-1611.

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

Grover, A., and Sharma R. (2006). Identification and Characterization of a Major Zn(II) Resistance Determinant of Mycobacterium smegmatis. J. Bact. 188: 7026-7032.

Halimaa, P., Y.F. Lin, V.H. Ahonen, D. Blande, S. Clemens, A. Gyenesei, E. Häikiö, S.O. Kärenlampi, A. Laiho, M.G. Aarts, J.P. Pursiheimo, H. Schat, H. Schmidt, M.H. Tuomainen, and A.I. Tervahauta. (2014). Gene Expression Differences between Noccaea caerulescens Ecotypes Help to Identify Candidate Genes for Metal Phytoremediation. Environ Sci Technol 48: 3344-3353.

Herzberg, M., L. Bauer, and D.H. Nies. (2014). Deletion of the zupT gene for a zinc importer influences zinc pools in Cupriavidus metallidurans CH34. Metallomics 6: 421-436.

Huang, L., C.P. Kirschke, Y. Zhang, and Y.Y. Yu. (2005). The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J. Biol. Chem. 280: 15456-15463.

Hudek L., Pearson LA., Michalczyk A., Neilan BA. and Ackland ML. (2013). Functional characterization of the twin ZIP/SLC39 metal transporters, NpunF3111 and NpunF2202 in Nostoc punctiforme. Appl Microbiol Biotechnol. 97(19):8649-62.

Huynh, C. and N.W. Andrews. (2008). Iron acquisition within host cells and the pathogenicity of Leishmania. Cell Microbiol 10: 293-300.

Huynh, C., D.L. Sacks, and N.W. Andrews. (2006). A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes. J Exp Med 203: 2363-2375.

Ivanov, R., T. Brumbarova, A. Blum, A.M. Jantke, C. Fink-Straube, and P. Bauer. (2014). SORTING NEXIN1 is required for modulating the trafficking and stability of the Arabidopsis IRON-REGULATED TRANSPORTER1. Plant Cell 26: 1294-1307.

Jacques, I., N.W. Andrews, and C. Huynh. (2010). Functional characterization of LIT1, the Leishmania amazonensis ferrous iron transporter. Mol Biochem Parasitol 170: 28-36.

Jenkitkasemwong, S., C.Y. Wang, B. Mackenzie, and M.D. Knutson. (2012). Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25: 643-655.

Kagara, N., N. Tanaka, S. Noguchi, and T. Hirano. (2007). Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer Sci. 98: 692-697.

Kambe, T., J. Geiser, B. Lahner, D.E. Salt, and G.K. Andrews. (2008). Slc39a1 to 3 (subfamily II) Zip genes in mice have unique cell-specific functions during adaptation to zinc deficiency. Am. J. Physiol. Regul Integr Comp Physiol 294: R1474-1481.

Karlinsey, J.E., M.E. Maguire, L.A. Becker, M.L. Crouch, and F.C. Fang. (2010). The phage shock protein PspA facilitates divalent metal transport and is required for virulence of Salmonella enterica sv. Typhimurium. Mol. Microbiol. 78: 669-685.

Korshunova, Y.O., D. Eide, W.G. Clark, M.L. Guerinot, and H.B. Pakrasi. (1999). The IRT1 protein from Arabidopsis thaliana is a metal transporter with a broad substrate range. Plant Mol. Biol. 40: 37-44.

Kumanovics, A., K.E. Poruk, K.A. Osborn, D.M. Ward, and J. Kaplan. (2006). YKE4 (YIL023C) encodes a bidirectional zinc transporter in the endoplasmic reticulum of Saccharomyces cerevisiae. J. Biol. Chem. 281: 22566-22574.

Lasswell, J., L.E. Rogg, D.C. Nelson, C. Rongey, and B. Bartel. (2000). Cloning and characterization of IAR1, a gene required for auxin conjugate sensitivity in Arabidopsis. Plant Cell 12: 2395-2408.

Li S., Zhou X., Huang Y., Zhu L., Zhang S., Zhao Y., Guo J., Chen J. and Chen R. (2013). Identification and characterization of the zinc-regulated transporters, iron-regulated transporter-like protein (ZIP) gene family in maize. BMC Plant Biol. 13:114.

Lin, S.J. and V.C. Culotta. (1996). Suppression of oxidative damage by Saccharomyces cerevisiae ATX2, which encodes a manganese-trafficking protein that localizes to Golgi-like vesicles. Mol. Cell. Biol. 16: 6303-6312.

Lin, W., J. Chai, J. Love, and D. Fu. (2010). Selective electrodiffusion of zinc ions in a Zrt-, Irt-like protein, ZIPB. J. Biol. Chem. 285: 39013-39020.

Liu, Z., H. Li, M. Soleimani, K. Girijashanker, J.M. Reed, L. He, T.P. Dalton, and D.W. Nebert. (2008). Cd2+ versus Zn2+ uptake by the ZIP8 HCO3--dependent symporter: kinetics, electrogenicity and trafficking. Biochem. Biophys. Res. Commun. 365: 814-820.

Lye, J.C., C.D. Richards, K. Dechen, C.G. Warr, and R. Burke. (2013). In vivo zinc toxicity phenotypes provide a sensitized background that suggests zinc transport activities for most of the Drosophila Zip and ZnT genes. J Biol Inorg Chem 18: 323-332.

Nam H., Wang CY., Zhang L., Zhang W., Hojyo S., Fukada T. and Knutson MD. (2013). ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders. Haematologica. 98(7):1049-57.

Nam, H. and M.D. Knutson. (2012). Effect of dietary iron deficiency and overload on the expression of ZIP metal-ion transporters in rat liver. Biometals 25: 115-124.

Nishida, S., Y. Morinaga, H. Obata, and T. Mizuno. (2011). Identification of the N-terminal region of TjZNT2, a Zrt/Irt-like protein family metal transporter, as a novel functional region involved in metal ion selectivity. FEBS J. 278: 851-858.

Pinilla-Tenas, J.J., B.K. Sparkman, A. Shawki, A.C. Illing, C.J. Mitchell, N. Zhao, J.P. Liuzzi, R.J. Cousins, M.D. Knutson, and B. Mackenzie. (2011). Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am. J. Physiol. Cell Physiol. 301: C862-871.

Plaza, S., K.L. Tearall, F.J. Zhao, P. Buchner, S.P. McGrath, and M.J. Hawkesford. (2007). Expression and functional analysis of metal transporter genes in two contrasting ecotypes of the hyperaccumulator Thlaspi caerulescens. J Exp Bot 58: 1717-1728.

Potocki S., Valensin D. and Kozlowski H. (2014). The specificity of interaction of Zn(2+), Ni(2+) and Cu(2+) ions with the histidine-rich domain of the TjZNT1 ZIP family transporter. Dalton Trans. 43(26):10215-23.

Radisky, D. and J. Kaplan. (1999). Regulation of transition metal transport across the yeast plasma membrane. J. Biol. Chem. 274: 4481-4484.

Ricachenevsky, F.K., P.K. Menguer, R.A. Sperotto, and J.P. Fett. (2015). Got to hide your Zn away: Molecular control of Zn accumulation and biotechnological applications. Plant Sci 236: 1-17.

Schaaf, G., A. Honsbein, A.R. Meda, S. Kirchner, D. Wipf, and N. von Wiren. (2006). AtIREG2 encodes a tonoplast transport protein involved in iron-dependent nickel detoxification in Arabidopsis thaliana roots. J. Biol. Chem. 281: 25532-25540.

Schmitt-Ulms, G., S. Ehsani, J.C. Watts, D. Westaway, and H. Wille. (2009). Evolutionary descent of prion genes from the ZIP family of metal ion transporters. PLoS One 4: e7208.

Schothorst, J., G.V. Zeebroeck, and J.M. Thevelein. (2017). Identification of Ftr1 and Zrt1 as iron and zinc micronutrient transceptors for activation of the PKA pathway in Saccharomyces cerevisiae. Microb Cell 4: 74-89.

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Taylor, K.M. and R.I. Nicholson. (2003). The LZT proteins: the LIV-1 subfamily of zinc transporters. Biochim. Biophys. Acta 1611: 16-30.

Ueno, M., K. Imadome, M. Iwakawa, K. Anzai, N. Ikota, and T. Imai. (2010). Vascular homeostasis regulators, Edn1 and Agpt2, are upregulated as a protective effect of heat-treated zinc yeast in irradiated murine bone marrow. J Radiat Res (Tokyo) 51: 519-525.

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Zhang, P., S. Tan, J.O. Berry, P. Li, N. Ren, S. Li, G. Yang, W.B. Wang, X.T. Qi, and L.P. Yin. (2014). An uncleaved signal peptide directs the Malus xiaojinensis iron transporter protein Mx IRT1 into the ER for the PM secretory pathway. Int J Mol Sci 15: 20413-20433.

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Examples:

TC#NameOrganismal TypeExample
2.A.5.1.1

High affinity zinc-regulated zinc uptake transporter, Zrt1 of 376 aas and 8 TMSs.  May be a transceptor with both transport and receptor (signal transduction) functions (Diallinas 2017; Schothorst et al. 2017). Activated at the transcriptional level by Yap1 and Ace1 (Gomes et al. 2005). Zrt1 may also transport, or influence the uptake of Cd2+ (Gomes et al. 2005).

Yeast, animals, plants

Zrt1 of Saccharomyces cerevisiae

 
2.A.5.1.10

ZIP family porter of 392 aas

Stramenopiles

ZIP family member of Phytophthora infestans (strain T30-4) (Potato late blight fungus)

 
2.A.5.1.11

Ferrous iron (Fe2+) transporting ZIP family member, LIT1, required for intracellular growth and virulence (Huynh et al. 2006). Also transports other metal ions less efficiently.  Residues involved in targetting and activity have been identified including His108, 283 and 309 (Jacques et al. 2010).

Euglenozoa

LIT1 of Leishmania major

 
2.A.5.1.12

Root iron transporter IRT1 of 364 aas and 9 TMSs.  Has an uncleaved signal peptide that targets the protein to the endoplasmic reticulum for transport to the plasma membrane (Zhang et al. 2014).

Plants

IRT1 of Malus xiaojinensis (apple)

 
2.A.5.1.13

Ferrous iron (Fe2+) uptake transporter of 347 aas and 9 TMSs.  Transports iron and possibly Cd2+ in this hyperaccumulating plant. Induced by iron deficiency and cadmium excess (Plaza et al. 2007).

IRT1 of Noccaea caerulescens (Alpine penny-cress) (Thlaspi caerulescens)

 
2.A.5.1.14

Low affinity zinc-regulated zinc uptake transporter, Zrt2 of 422 aas and 7 TMSs. Active in zinc-replete cells and is time-, temperature- and concentration-dependent.  It prefers zinc over other metals as its substrate (Zhao and Eide 1996).

Zrt2 of Saccharomyces cerevisiae

 
2.A.5.1.15

Zinc transporter, Zrt1 of 468 aas and 7 TMSs.  Receives Zn2+ from the secreted, extracellular zincophore protein, Pra1 for uptake of the metal.  The binding site in Pra1 is in the C-terminal region of this 299 aa protein (Łoboda and Rowińska-Żyrek 2017). Pra1 is a cell surface protein with a single N-terminal TMS involved in the host-parasite interaction during candidal infection. With MP65,  it represents a major component of the biofilm matrix. It sequesters zinc from host tissues and mediates leukocyte adhesion and migration (Citiulo et al. 2012).

Zrt1/Pra1 of Candida albicans and Candida dubliniensis (Yeast)

 
2.A.5.1.2

Iron regulated Fit1-mediated plasma membrane high affinity Fe2+ uptake transporter, Irt1 (also takes up Co2+, Mn2+, Zn2+ and possibly Cd2+) (Korshunova et al., 1999; Schaaf et al., 2006; Halimaa et al. 2014).  Targetted to the plasma membrane by Sorting nexin1 (Snx1; Q9FG38) (Ivanov et al. 2014).

Plants, animals, yeast

Irt1 of Arabidopsis thaliana

 
2.A.5.1.3Zinc/iron uptake transporter, Zip1 (Grass et al., 2005; Grotz et al., 1998)PlantsZip1 of Arabidopsis thaliana (O81123)
 
2.A.5.1.4Iron-regulated Fit1-mediated (coregulated with Irt1) vacuolar high-affinity Fe2+ efflux (from the vacuole into the cytoplasm) transporter, Irt2 (also transports Zn2+ (Schaaf et al., 2006)PlantsIrt2 of Arabidopsis thaliana (O81850)
 
2.A.5.1.5

Zinc (Zn2+) uptake transporter, ZIP8 (Ueno et al. 2010)

Plants

ZIP8 of Oryza sativa (A3BI11)

 
2.A.5.1.6

The Zn2+/Cd2+ transporter, ZNT1 (Nishida et al., 2011).  The histidine-rich loop between TMSs3 and 4 binds Cu2+ > Zn2+ > Ni2+ (Potocki et al. 2014).

Plants

ZNT1 of Thlaspi caerulescens (Q9M7J1)

 
2.A.5.1.7

The Zn2+/Cd2+ transporter ZNT2 (Nishida et al., 2011)

Plants

ZNT2 of Thlaspi caerulescens (Q92XE7)

 
2.A.5.1.8

Zinc-regulated transporter 1 (High-affinity zinc transport (uptake) protein Zrt1) (Boch et al. 2008).

Yeast

Zrt1 of Schizosaccharomyces pombe

 
2.A.5.1.9

Protein ZntC

Amoeba

ZntC of Dictyostelium discoideum

 
Examples:

TC#NameOrganismal TypeExample
2.A.5.2.1

Golgi Mn2+ homeostasis protein (probably pumps Mn2+ into cytoplasm), ATX2 (Eide, D.J, 1998)

Yeast

ATX2 of Saccharomyces cerevisiae

 
Examples:

TC#NameOrganismal TypeExample
2.A.5.3.1

Growth arrest-inducible protein, ZIP2 of 309 aas.  Zinc dyshomeostasis leads to augmented production of proinflammatory cytokines, promoting chronic inflammation and increasing the susceptibility to age-related diseases. ZIP2 plays a role in the immune system, especially during zinc deficiency, while a polymorphism in the coding region of ZIP2 (Gln/Arg/Leu) is associated with severe carotid artery disease (Giacconi et al. 2015).

Animals

SLC39A2 of Homo sapiens

 
2.A.5.3.2

Zn2+ uptake transporter, Zip1 (abundantly expressed; involved in zinc homeostasis rather than acquisition of dietary Zn2+) (Gaither and Eide, 2000).  Mouse Zip1, 2 and 3 play important noncompensatory roles under conditions of zinc deficiency (Kambe et al. 2008).

Animals

SLC39A1 of Homo sapiens

 
2.A.5.3.3Zn2+ uptake transporter, Zip3 (poorly expressed; involved in Zn2+ homeostasis) (Dufner-Beattie et al., 2003).AnimalsSLC39A3 of Homo sapiens
 
2.A.5.3.4

Zinc transporter 1 (ZRT/IRT-like protein 1) (OsZIP1)

Plants

ZIP1 of Oryza sativa

 
2.A.5.3.5Zinc transporter ZIP1 (DrZIP1) (Solute carrier family 39 member 1) (Zrt- and Irt-like protein 1) (ZIP-1)Animals

Slc39a1 of Danio rerio

 
2.A.5.3.6

Zip1 (ZIP42C.1) Zn2+ uptake transporter of 352 aas; Zn/Fe regulated (Lye et al. 2013; Dechen et al. 2015).

Animals

Zip1 of Drosophila melanogaster (Fruit fly)

 
2.A.5.3.7

ZIP family member of 437 aas

Alveolata

ZIP protein of Cryptosporidium parvum

 
2.A.5.3.8

Zip3 or Zip89B Zinc uptake porter of 495 aas.

Animals

Zip3 of Drosophila melanogaster

 
Examples:

TC#NameOrganismal TypeExample
2.A.5.4.1

Zip4 Zn2+ uptake transporter (Acrodermatitis enteropathica zinc-deficiency disease protein) (Dufner-Beattie et al., 2003).  The large cytoplasmic loop is an intrinsically disordered zinc binding domain (Bafaro et al. 2015). A modeled ZIP4 dimer possibly resembles the twelve TMS monomeric PiPT of the MFS, as a likely structural homologue (Antala et al. 2015).

Animals

SLC39A4 of Homo sapiens

 
2.A.5.4.10

Zn2+ transporter, Zip5 (540aas; 1+3+3 TMSs; processed to a 3+3 TMS protein) (Basolateral membrane; carries out serosal to mucosal transport)

AnimalsSLC39A5 of Homo sapiens
 
2.A.5.4.11

The Zn2+ and Cd2+ uptake porter, ZipB (nonsaturable; electrogenic) (Lin et al. 2010).

Bacteria

ZipB of Bordetella bronchispetica (Q2KXZ6)

 
2.A.5.4.12

ZIP13 Zn influx porter, an 8TMS homodimer with N- and C-termini facing the lumen of the Golgi. Important for connective tissue development. Its loss causes the Spondylocheiro dysplastic form of Ehlers-Danlos syndrome (Bin et al., 2011).

AnimalsSLC39A13 of Homo sapiens
 
2.A.5.4.13

Solute carrier family 39, SLC39 (zinc transporter), member 6, ZIP6.  May be an evoltionary precursor of mammalian prion proteins (Schmitt-Ulms et al. 2009).

Animals

SLC39A6 of Homo sapiens

 
2.A.5.4.14 solute carrier family 39 (zinc transporter), member 12AnimalsSLC39A12 of Homo sapiens
 
2.A.5.4.15

Zinc/iron/manganese/cadmium transporter ZIP8 (BCG-induced integral membrane protein in monocyte clone 103 protein) (LIV-1 subfamily of ZIP zinc transporter 6, LZT-Hs6; Solute carrier family 39 member 8; Zrt- and Irt-like protein 8) (Jenkitkasemwong et al. 2012).  Functions in Cd2+ uptake, cell toxicity and hypertension (Zhang et al. 2015).

Animals

SLC39A8 of Homo sapiens

 
2.A.5.4.16

Zinc transporter Foi (Protein fear-of-intimacy) (Protein kastchen)

Animals

Foi of Drosophila melanogaster

 
2.A.5.4.17

Zinc importer, ZupT of 291 aas and 6 TMSs (Herzberg et al. 2014).

ZupT of Cupriavidus metallidurans (Ralstonia metallidurans)

 
2.A.5.4.2

Zinc transporter, LIV1 (essential for the nuclear localization of the zinc-finger protein Snail, a master regulator of the epithelial-mesenchymal transition in zebrafish gastrulation) (Yamashita et al., 2004)

Animals

LIV1 in Danio rerio (Q6L8F3)

 
2.A.5.4.3

Zip7 Golgi Zn2+ uptake (into the cytoplasm) transporter (Ke4, Slc39a7) (Huang et al., 2005). This protein can substitute for Iar1, the indole acetic acid-alanine resistance protein, of A. thaliana (Lasswell et al., 2000)

Animals

SLC39A7 of Homo sapiens

 
2.A.5.4.4Bidirectional endoplasmic reticular Zn2+ transporter, Yke4 (346 aas; Kumanovics et al., 2006)YeastYke4 (YIL023c) of Saccharomyces cerevisiae (P40544)
 
2.A.5.4.5

Zip14 Zn2+/Fe2+/Mn2+/Cd2+ uptake transporter (mobilized to the sinusoidal membrane of the hepatocyte during acute inflammation) (Jenkitkasemwong et al. 2012; Pinilla-Tenas et al., 2011); KM for Fe2+= 0.002 μM.  The prion gene family may have descended from an ancestral LZT gene (Ehsani et al. 2012).  The gene is upregulated by iron loading (Nam et al. 2013). LIV-1 ZIP ectodomain shedding in prion-infected mice resembles the cellular response to transition metal starvation (Ehsani et al. 2012).  Zip14 promotes cellular assimilation of iron from transferrin (Zhao et al. 2010) and also plays a role in maintaining manganese homeostasis (Xin et al. 2017).

.

Animals

SLC39A14 of Homo sapiens

 
2.A.5.4.6

Zinc transporter, Zip10 (plays an essential role in the migratory activity of highly metastatic breast cancer cells) (Kagara et al., 2007).  May be an evolutionary precursor of prion proteins in mammals (Schmitt-Ulms et al. 2009).

Animals

SLC39A10 of Homo sapiens

 
2.A.5.4.7The indole acetic acid-alanine resistance protein 1, Iar1 (Lasswell et al., 2000)PlantsIar1 of Arabidopsis thaliana (Q9M647)
 
2.A.5.4.8The divalent cation (M2+): bicarbonate (HCO3-) transporter (M2+:HCO3- = 1:2). Transports Cd2+ and Zn2+, and probably Cu2+, Pb2+, and Hg2+ (based on competitive inhibition studies (Liu et al., 2008))AnimalsZip8 of Mus musculus (Q91W10)
 
2.A.5.4.9

Probable Zn2+ transporter, Zip13 (SLC39A13). Mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS) (Fukada et al., 2008).

Animals

Zip13 of Mus musculus (Q8BZH0)

 
Examples:

TC#NameOrganismal TypeExample
2.A.5.5.1

Broad specificity heavy metal divalent cation uptake transporter, ZupT (Fe2+, Co2+, Mn2+, Cd2+ and Zn2+ are transported) (Grass et al., 2005). Point mutations change the specificity and kinetics of metal uptake (Taudte and Grass, 2010). Important for virulence in Salmonella (Karlinsey et al., 2010).

Bacteria

ZupT of E. coli (P0A8H3)

 
2.A.5.5.2Zinc transporter ZIP11 (Solute carrier family 39 member 11) (Zrt- and Irt-like protein 11) (ZIP-11)AnimalsSLC39A11 of Homo sapiens
 
2.A.5.5.3

Zinc-regulated transporter 3, Zrt3 (Vacuolar membrane zinc transporter)

Fungi

Zrt3 of Saccharomyces cerevisiae

 
2.A.5.5.4Probable zinc transporter zip2Yeastzip2 of Schizosaccharomyces pombe
 
2.A.5.5.5Zinc transporter ZupT

Verrucomicrobia

ZupT of Akkermansia muciniphila

 
2.A.5.5.6

ZIP11, Zinc permease of 251 aas and 8 TMSs (Hudek et al. 2013).  Transports zinc as well as cadmium, cobalt, copper, manganese and nickel.

Cyanobacteria

Zinc/Iron permease of Nostoc punctiforme

 
2.A.5.5.7

Zip family protein of 651 aas, ZIL2

Green Algae

ZIL2 of Chlamydomonas reinhardtii (Chlamydomonas smithii)

 
2.A.5.5.8

Zip family homologue of 553 aas and 16 TMSs

Green Algae

ZIP family homologue of Volvox carteri

 
Examples:

TC#NameOrganismal TypeExample
2.A.5.6.1

Zip family member, ZIP9 (SLC39A9) (307aas; 8 TMSs).  The orthologue, Zip9, in the atlantic croaker (Micropogonias undulatus) is an androgen receptor that mediates testosterone-induced apoptosis of female ovarian follicle cells (Berg et al. 2014).

Animals

SLC39A9 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample