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 8 TMSs. 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 such as humans, 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). ZIP proteins form homo- or
heterodimers with 8 transmembrane domains and extra-/intracellular
domains of various lengths. Several ZIP members show specific
extracellular domains composed of two subdomains, a helix-rich domain
and proline-alanine-leucine (PAL) motif-containing domain (Bin et al. 2018).
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 .
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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
ZIP family porter of 392 aas
ZIP family member of Phytophthora infestans (strain T30-4) (Potato late blight fungus)
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).
LIT1 of Leishmania major
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).
IRT1 of Malus xiaojinensis (apple)
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)
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
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)
Zinc uptake transporter of 352 aas and 8 TMSs. RaZIP1 is a high-affinity plasma membrane transporter specialized in Zn2+ uptake, but also taking up Cd2+ with lower affinity (Leonhardt et al. 2018).
Zip1 of Russula atropurpurea
Zinc/Iron/Cadmium ion transporter protein IRT1 of 355 aas and 9 TMSs. Regulated by MAP kinase 4 which therefore regulates cell death in the presence of Cd2+ (Zhang et al. 2019).
IRT1 of Nicotiana tabacum (Common tobacco)
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.5.1.3||Zinc/iron uptake transporter, Zip1 (Grass et al., 2005; Grotz et al., 1998)||Plants||Zip1 of Arabidopsis thaliana (O81123)|
|2.A.5.1.4||Iron-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)||Plants||Irt2 of Arabidopsis thaliana (O81850)|
Zinc (Zn2+) uptake transporter, ZIP8 (Ueno et al. 2010)
ZIP8 of Oryza sativa (A3BI11)
The Zn2+/Cd2+ transporter, ZNT1 (Nishida et al., 2011). The histidine-rich loop between TMSs 3 and 4 binds Cu2+ > Zn2+ > Ni2+ (Potocki et al. 2014).
ZNT1 of Thlaspi caerulescens (Q9M7J1)
The Zn2+/Cd2+ transporter ZNT2 (Nishida et al., 2011)
ZNT2 of Thlaspi caerulescens (Q92XE7)
Zinc-regulated transporter 1 (High-affinity zinc transport (uptake) protein Zrt1) (Boch et al. 2008).
Zrt1 of Schizosaccharomyces pombe
ZntC of Dictyostelium discoideum
Golgi Mn2+ homeostasis protein (probably pumps Mn2+ into cytoplasm), ATX2 (Eide, D.J, 1998)
ATX2 of Saccharomyces cerevisiae
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).
SLC39A2 of Homo sapiens
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).
SLC39A1 of Homo sapiens
Zn2+ uptake transporter, Zip3 (poorly expressed; involved in Zn2+ homeostasis) (Dufner-Beattie et al., 2003). This protein plays an ancillary role in zinc homeostasis in mice (Dufner-Beattie et al. 2005).
SLC39A3 of Homo sapiens
Zinc transporter 1 (ZRT/IRT-like protein 1) (OsZIP1)
ZIP1 of Oryza sativa
|2.A.5.3.5||Zinc transporter ZIP1 (DrZIP1) (Solute carrier family 39 member 1) (Zrt- and Irt-like protein 1) (ZIP-1)||Animals|
Slc39a1 of Danio rerio
Zip1 (ZIP42C.1) Zn2+ uptake transporter of 352 aas; Zn/Fe regulated (Lye et al. 2013; Dechen et al. 2015).
Zip1 of Drosophila melanogaster (Fruit fly)
ZIP family member of 437 aas
ZIP protein of Cryptosporidium parvum
Zip3 or Zip89B Zinc uptake porter of 495 aas.
Zip3 of Drosophila melanogaster
Putative zinc transporter of 298 aas and 8 TMSs.
Zn2+ transporter of Entamoeba histolytica
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).
SLC39A4 of Homo sapiens
Zn2+ transporter, Zip5 (540aas; 1+3+3 TMSs; processed to a 3+3 TMS protein) (Basolateral membrane; carries out serosal to mucosal transport)
|Animals||SLC39A5 of Homo sapiens|
The Zn2+ and Cd2+ uptake porter, ZipB (nonsaturable; electrogenic) (Lin et al. 2010). Water-mediated zinc transport through the ZipB channel sugests an essential role of solvated water molecules in driving zinc coordination dynamics and transmembrane crossing (Gupta et al. 2019).
ZipB of Bordetella bronchispetica (Q2KXZ6)
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).
|Animals||SLC39A13 of Homo sapiens|
Solute carrier family 39, SLC39 (zinc transporter), member 6, ZIP6. May be an evoltionary precursor of mammalian prion proteins (Schmitt-Ulms et al. 2009).
SLC39A6 of Homo sapiens
|2.A.5.4.14|| solute carrier family 39 (zinc transporter), member 12||Animals||SLC39A12 of Homo sapiens|
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).
SLC39A8 of Homo sapiens
Zinc transporter Foi (Protein fear-of-intimacy) (Protein kastchen)
Foi of Drosophila melanogaster
Zinc importer, ZupT of 291 aas and 6 TMSs (Herzberg et al. 2014).
ZupT of Cupriavidus metallidurans (Ralstonia metallidurans)
Zinc transporter, ZIPT-7.1; regulates sperm activation in nematodes. In spermatids, inactive ZIPT-7.1 localizes to the intracellular membranous organelles, which contain higher levels of zinc than the cytoplasm. When sperm activation is triggered, ZIPT-7.1 activity increases, releasing zinc from internal stores. The resulting increase in cytoplasmic zinc promotes activatioin (Zhao et al. 2018).
ZIPT-7.1 of Caenorhabditis elegans
ZIP Zinc transporter of 231 aas and 8 TMSs
ZIP transporter of Lokiarchaeum sp. GC14_75
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)
LIV1 in Danio rerio (Q6L8F3)
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)
SLC39A7 of Homo sapiens
|2.A.5.4.4||Bidirectional endoplasmic reticular Zn2+ transporter, Yke4 (346 aas; Kumanovics et al., 2006)||Yeast||Yke4 (YIL023c) of Saccharomyces cerevisiae (P40544)|
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). SLC39A14 is essential for efficient Mn2+ uptake by the liver and pancreas, and its deficiency results in impaired Mn2+ excretion and accumulation of the metal in other tissues (Jenkitkasemwong et al. 2018). Mutations cause hypermanganesemia associated with infantile onset dystonia (Juneja et al. 2018).
SLC39A14 of Homo sapiens
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).
SLC39A10 of Homo sapiens
|2.A.5.4.7||The indole acetic acid-alanine resistance protein 1, Iar1 (Lasswell et al., 2000)||Plants||Iar1 of Arabidopsis thaliana (Q9M647)|
|2.A.5.4.8||The 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))||Animals||Zip8 of Mus musculus (Q91W10)|
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).
Zip13 of Mus musculus (Q8BZH0)
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).
ZupT of E. coli (P0A8H3)
|2.A.5.5.2||Zinc transporter ZIP11 (Solute carrier family 39 member 11) (Zrt- and Irt-like protein 11) (ZIP-11)||Animals||SLC39A11 of Homo sapiens|
Zinc-regulated transporter 3, Zrt3 (Vacuolar membrane zinc transporter)
Zrt3 of Saccharomyces cerevisiae
|2.A.5.5.4||Probable zinc transporter zip2||Yeast||zip2 of Schizosaccharomyces pombe |
|2.A.5.5.5||Zinc transporter ZupT|
ZupT of Akkermansia muciniphila
ZIP11, Zinc permease of 251 aas and 8 TMSs (Hudek et al. 2013). Transports zinc as well as cadmium, cobalt, copper, manganese and nickel.
Zinc/Iron permease of Nostoc punctiforme
Zip family protein of 651 aas, ZIL2
ZIL2 of Chlamydomonas reinhardtii (Chlamydomonas smithii)
Zip family homologue of 553 aas and 16 TMSs
ZIP family homologue of Volvox carteri
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).
SLC39A9 of Homo sapiens