Bacteria

ZitB of E. coli (P75757)

The major Zn²⁺ resistance determinant, ZitA (Grover and Sharma, 2006)

Bacteria

ZitA of Mycobacterium smegmatis (A0QQH3)

Dimeric Zn²⁺ efflux carrier of 299 aas and 5 TMSs, CzcD (Martin and Giedroc 2016).

CzcD of Streptococcus pneumoniae

Yeast

Cotl of Saccharomyces cerevisiae

Yeast

Zrclp (ZnrP) of Saccharomyces cerevisiae

Plasma membrane Zn²⁺ efflux permease.  Substituing H43 with N (asn) changed the specificity from Zn²⁺ to Mn²⁺, and this difference was found in the Mn²⁺-specific metal ion exporter, ZnT10 (TC# 2.A.4.2.5) (Nishito et al. 2016). Expression on the cell surface is controlled by cellular zinc levels (Nishito and Kambe 2019).

Animals

ZnT1 of Rattus norvegicus

Animals

CDF-1 of Caenorhabditis elegans (Q95QW4)

Solute carrier family 30, member 10, ZnT10.  Manganese efflux transporteer of 485 aas and 6 TMSs in a 4 + 2 TMS arrangement with two long hydrophilic regions between residues 135 and 240, and residues 300 and 485 (Nishito et al. 2016).  Homozygous mutations lead to the development of familial manganese Mn²⁺-induced parkinsonism; it is a cell surface-localized Mn²⁺ efflux transporter, and parkinsonism-causing mutations block its trafficking and efflux activity. Residues in the transmembrane and C-terminal domains together confer optimal Mn²⁺ transport capability (Zogzas et al. 2016). Residues involved in Mn²⁺ binding in the transmembrane domain have been identified, and they differ in position and nature from the Zn²⁺ binding site in Zn²⁺ transporting members of the CDF family (Zogzas and Mukhopadhyay 2018). Loss of ZnT10 expression caused by autosomal mutations in the ZnT10 gene leads to hypermanganesemia in multiple organs (Levy et al. 2019). The cellular transport of Mn²⁺ is coupled to a reciprocal movement of Ca²⁺. Replacing a single asparagine residue in ZnT10 (Asn-43) with threonine (ZnT10 N43T) converted the Mn²⁺/Ca²⁺ exchanger into an uncoupled channel permeable to both Ca²⁺ and Mn²⁺ (Levy et al. 2019). It is expressed in the CNS (Sreedharan et al. 2011).

Animals

SLC30A10 or ZnT10 of Homo sapiens

Zinc transporter 1 (ZnT-1 or ZnT1) (Solute carrier family 30 member 1). The loss of the sialic acid transporter SLC35A1/CST (TC# 2.A.7.12.11) and the zinc transporter, ZnT1, affected cell survival upon infection with cytolytic vesicular stomatitis virus (VSV). Both of these transporters seem to play a role in the apoptotic response induced by VSV (Moskovskich et al. 2019). ZnT1 functions by Zn²⁺:H⁺ antiport and has a C-terminal hydrophilic domain that is a dimer in solution with a V-shaped core (Cotrim et al. 2021). There are 10 ZnT proteins in humans, but only ZnT1 is a zinc exporter in the plasma membrane, and only ZnT10 is a Mn²⁺ exporter; a reliable in vitro assay has been developed for measuring Zn²⁺ uptake (Ben Yosef et al. 2023).  Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism (Rege et al. 2023).

Animals

SLC30A1 of Homo sapiens

ZnT63C Zinc exporter, ZnT1, of 545 aas and 5 putative TMSs (Lye et al. 2013; Dechen et al. 2015).

Animal

ZnT63C of Drosophila melanogaster

Vacuolar CDF1 transporter.  Transports Zn²⁺, Co²⁺ and Cd²⁺ but not Mn²⁺, of 487 aas and 6 TMSs (Sácký et al. 2016).

CDF1 of Russula atropurpurea

The plasma membrane zinc efflux system, ZnT-1, of 485 aas and 6 predicted TMSs with a large histidine-rich intracellular loop between TMSs 4 and 5 and intracellular C- and N-termini (Balesaria and Hogstrand 2006).

ZnT-1 of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes)

Vesicular Zn²⁺ uptake (into endosomal/lysosomal vesicles) permease, ZnT2. There are two isoforms due to alternative splicing, 35 kDa (plasma membrane localized) and 42 kDa (endosome/secretory compartment localized) (Lopez and Kelleher, 2009).

ZnT2 of Rattus norvegicus

CDF transporter, MTP1 of 640 aas and 6 TMSs.  It transports zinc (Zn²⁺) and cobalt (Co²⁺) (Ibuot et al. 2020).

MTP1 of Chlamydomonas reinhardtii

Zn²⁺  Transporter, LbrM31, of 443 aas and 6 or 7 TMSs.

Euglenoza

LbrM31 of Leishmania braziliensis (A4HJM3)

Zinc transporter, Ttm-1, of 410 aas and 6 TMSs in a 2 + 2 + 2 TMS arrangement. It promotes excretion of zinc from intestinal cells into the intestinal lumen in response to increased dietary zinc (Roh et al. 2013). It is also involved in cadmium resistance, possibly by promoting its transport from cells (Huffman et al. 2004). It is also involved in resistance to B. thuringiensis pore-forming toxin Cry5B downstream of the sek-1 and pmk-1 MAPK kinase pathway.

Ttm-1 of Caenorhabditis elegans

Zn²⁺, Fe²⁺ and Co²⁺ exporter, AitP, of 321 aas and 6 TMSs. The N₂-fixing bacteria, Sinorhizobium meliloti, is a suitable model to determine the roles of Co²⁺-transporting Co-eCDF in Fe²⁺ homeostasis because it has a putative member of this subfamily, AitP, and two specific Fe²⁺-export systems. An insertional mutant of AitP showed Co²⁺ sensitivity and accumulation, Fe accumulation and hydrogen peroxide sensitivity, but not Fe²⁺ sensitivity, despite AitP being a bona fide low affinity Fe²⁺ exporter as demonstrated by the kinetic analyses of Fe²⁺ uptake into everted membrane vesicles (Mihelj et al. 2023).

Vesicular Zn²⁺ uptake (into synaptic vesicles) permease, ZnT3 (SLC30A subfamily). ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory (Sindreu et al., 2011).

Plant root and leaf vacuolar Zn²⁺ transporter, ZAT-1 or MTP1 (metal tolerance protein 1) (Desbrosses-Fonrouge et al., 2005). Loss of the cytoplasmic histidine-rich loop, where 4 Zn²⁺ (or Ni²⁺ or Co²⁺) bind, stimulates transport activity (Kawachi et al., 2008), presumably providing a feedback sensor of cytoplasmic Zn²⁺ (Tanaka et al. 2013). The barley orthologue has broader metal specificity (Podar et al., 2012). Critical residues for function, ion selectivity and structure have been identified (Kawachi et al., 2012). In Citrus sinensis, expression is induced by Cd²⁺ (Fu et al. 2017).

Plants

MTP1 of Arabidopsis thaliana
(Q9ZT63)

Homodimeric solute carrier family 30 (zinc transporter), member 8, ZnT8 or ZnT-8.  An inherited R325W mutant gives aberant zinc transport in pancreatic beta cells (Weijers 2010). It is chiefly expressed in pancreatic islet cells, where it mediates zinc (Zn²⁺) uptake into secretory granules. It plays a role in glucose tolerance (Mitchell et al. 2016). ZnT8 is one of four human vesicular zinc transporters. It supplies millimolar zinc concentrations to insulin granules in pancreatic beta-cells, affecting insulin processing, crystallisation, and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc, and channels zinc to the transport site in the transmembrane domain (Parsons et al. 2018). The variant, W325R, in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. The CTDs of the WT and mutant proteins form tetramers which are stabilized by zinc binding and exhibit negligible differences in their secondary structural content and zinc-binding affinities in solution (Ullah et al. 2020). Xue et al. 2020 described cryo-EM structures in both outward- and inward-facing conformations. HsZnT8 forms a dimeric structure with four Zn²⁺ binding sites within each subunit with a highly conserved primary site in the TMD housing the Zn²⁺ substrate. An interfacial site between the TMD and the CTD modulates the Zn²⁺ transport activity. Two adjacent sites buried in the cytosolic domain are chelated by conserved residues from CTD and the His-Cys-His (HCH) motif from the N-terminal segment of the neighboring subunit. A comparison of the outward- and inward-facing structures reveals that the TMD of each subunit undergoes a large structural rearrangement, allowing for alternating access to the primary Zn²⁺ site during the transport cycle (Xue et al. 2020). The C-terminal domain of the human zinc transporter hZnT8 Is structurally indistinguishable from its disease risk variant (R325W) (Ullah et al. 2020). The dynamics of ZnT8 have been studied (Sala et al. 2021), revealing that packing of the TMSs affects channel accessibility from the cytosol. The dimer interface that keeps the two TM channels in contact became looser in both variants upon zinc binding to the transport site, suggesting that this may be an important step toward the switch from the inward- to the outward-facing states of the protein (Sala et al. 2021). The C-terminal cysteines, which are part of the cytosolic domain, are involved in a metal chelation and/or acquisition mechanism, and provides the first example of metal-thiolate coordination chemistry in zinc transporters (Catapano et al. 2021). Human ZnT8 (SLC30A8) is a diabetes risk factor and a zinc transporter (Daniels et al. 2020). ZnT8 loss of function mutations increase resistance of human embryonic stem cell-derived beta cells to apoptosis unswe low zinc conditions (Sui et al. 2023).  Protons may disrupt Zn²⁺ coordination at the transmembrane Zn²⁺-binding site in the lumen-facing state, thus facilitating Zn²⁺ release from ZnT8 into the lumen (based on the cryoEM structure of the Xenopus tropecalis ZnT8 (Zhang et al. 2023).

.

Animals

SLC30A8 of Homo sapiens

Metal tolerance protein 4, MTP4, of 386 aas.  Exports Zn²⁺ and Cd²⁺ (Migocka et al. 2015).  MTP1 transports the same two ions but is less restrictive with respect to the tissues in which the protein is synthesized.

MTP4 of Cucumis sativus (Cucumber)

Co²⁺ resistance protein, DmeF, of 382 aas and 6 TMSs. Co²⁺ export appears to be its dominant physiological function, but it may also export other heavy metal ions such as Zn²⁺ and Cd²⁺ (Munkelt et al. 2004).

DmeF of Cupriavidus metallidurans (Ralstonia metallidurans)

Heteromeric nuclear/ER Zn²⁺ uptake permease, Msc2/Zrg17 (Ellis et al., 2005).  Zrg17 is also called Meiotic sister-chromatid recombination-related protein or metal cation transporter Msc2p of 724 aas and 15 TMSs in a 7 + 2 + 6 TMS arrangement.  Only the last 6 TMSs are homologous to CDF transporters.

Yeast

Msc2/Zrg17 heteromeric Zn²⁺ transporter of Saccharomyces cerevisiae
Msc2 (Q03455)
Zrg17 (P53735)

Golgi/secretory granule Zn²⁺ uptake (into Golgi or granules) permease, ZnT5 or ZTL1 (ZnT5 forms heterooligomers with ZnT6) (Ellis et al., 2005; Ishihara et al., 2006; Fukunaka et al. 2009) (Variant B catalyzes bidirectional transport (Valentine et al., 2007) )

Animals

SLC30A5 or ZnT5 of Homo sapiens

Golgi/secretory granule/endoplasmic reticulum Zn²⁺ uptake (into Golgi, the ER, or granules) permease, ZnT6.  ZnT6 forms heterooligomers with ZnT5 (Ellis et al., 2005; Ishihara et al., 2006; Fukunaka et al. 2009).

Animals

SLC30A6 of Homo sapiens

Golgi/secretory granule Zn²⁺ uptake (into Golgi or granules) permease, ZnT7 (Ishihara et al., 2006). Bui et al. 2023 presented the 2.2-3.1 Å-resolution cryo-EM structures of the human Zn²⁺/H⁺ antiporter ZnT7 in Zn²⁺-bound and unbound forms. Cryo-EM analyses show that hZnT7 exists as a dimer via tight interactions in both the cytosolic and transmembrane (TM) domains of two protomers, each of which contains a single Zn²⁺-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn²⁺ entry in the inward-facing conformation and widens the luminal cavity for Zn²⁺ release in the outward-facing conformation. An exceptionally long cytosolic histidine-rich loop, characteristic of hZnT7, binds two Zn²⁺ ions, seemingly facilitating Zn²⁺ recruitment to the TM metal transport pathway. These structures allow mechanisms of hZnT7-mediated Zn²⁺ uptake into the Golgi to be proposed (Bui et al. 2023).

Animals

SLC30A7 of Homo sapiens

Metal tolerance protein C2 (AtMTPc2) (AtMTP5).  Forms a large, active, heteromeric complex with MTP12 in the golgi and pumps Zn²⁺ into this organelle (Fujiwara et al. 2015).  MTP12 has 798 aas and 14 TMSs.  Its UniProt acc # is A0A0A8IL98. In Citrus sinensis, expression is induced by Zn²⁺ in roots (Fu et al. 2017).

Plants

MTPC2 or MTP5 of Arabidopsis thaliana

Lead (Pb²⁺) efflux transporter of 211 aas, PbtF (Hložková et al. 2013).

Proteobacteria

PbtF of Achromobacter xylosoxidans

Uncharacterized protein of 701 aas and 16 TMSs, where the last 6 TMSs are homologous to CDF transporters.

UP of Eremothecium cymbalariae (Yeast)

Metal tolerance protein 12, MTP12 of 300 aas and 6 TMSs.  In Citrus sinensis, expression is induced by Cd²⁺ in roots (Fu et al. 2017).

MTP12 of Arabidopsis thaliana

Golgi/endomembrane Mn²⁺-specific CDF transporter (394 aas) (Peiter et al., 2007).  A rice homologue, MTP8.1, has been characterized (Chen et al. 2016).

Plants

MTP11.1 of Populus trichocarpa (A4ZUV2)

CDF2 transporter for Zn²⁺ and Co²⁺ but not Cd²⁺ or Mn²⁺ of 417 aas and 5 TMSs (Sácký et al. 2016).

CDF2 of Russula atropurpurea

MTP8.1 is a tonoplast-localized manganese transporter of 400 aas and 6 TMSs. Critical residues for function in the rice orthologue have been identified (Chen et al. 2016).

MTP8.1 of Hordeum vulgare (Barley)

Metal tolerance protein 8, MTP8, of 411 aas and 6 TMSs. In Citrus sinensis, expression is induced by Mn²⁺ in roots (Fu et al. 2017). In A. thaliana, MPT8 determines the localization of manganese and iron in seeds (Chu et al. 2017). The endodermal vacuole is the iron and manganese storage compartment in the A. thaliana embryo (Roschzttardtz et al. 2009).

MTP8 in Arabidopsis thaliana

Metal tolerance protein 11, MTP11, of 298 aas and 5 TMSs. In Citrus sinensis, expression is induced by Zn²⁺ in leaves (Fu et al. 2017).

MTP11 of Arabidopsis thaliana

CDF transporter, MTP3, of 458 aas and 7 TMSs.  It transports Mn²⁺, Zn²⁺ and Co²⁺ (Ibuot et al. 2020).

MTP3 of Chlamydomonas reinhardtii (Chlamydomonas smithii)

Mn²⁺ transporting CDF porter, MTP4, of 538 aas and 6 TMSs.

MTP4 of Chlamydomonas reinhardtii (Chlamydomonas smithii)

Metal tolerance protein 4 (MTP4) of 412 aas and 6 central TMSs  It has dual functions in maintaining zinc homeostasis in tea plants (Li et al. 2024).

MTP4 of Citrus unshi

CDF transporter, ZnT9 (568 aas) (Montanini et al., 2007). Mutations cause autosomal recessive cerebro-renal syndrome and affect intracellular Zinc homeostasis (Perez et al. 2017). Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9, causing a complex movement disorder, developmental regression, oculomotor abnormalities, and renal impairment (Steel et al. 2023).

Animals

SLC30A9 of Homo sapiens

Metal tolerance protein C4, MTPC4 of 457 aas and 6 TMSs.  It is involved in sequestration of excess metal ions, including Zn²⁺ in the cytoplasm into vacuoles to maintain metal homeostasis.

MTPC4 of Arabidopsis thaliana (Mouse-ear cress)

Zn²⁺/Cd²⁺/Hg²⁺/Fe²⁺:H⁺ antiporter, YiiP or FieF (Chao and Fu, 2004b; Grass et al., 2005; Wei et al., 2004; Wei and Fu, 2006). The structure (3.8 Å resolution) reveals a homodimer interconnected at the cytoplasmic domain through four Zn²⁺ ions. A 6 TMS bundle features of a tetrahedral Zn²⁺ binding site (Lu and Fu, 2007). The gated water access to the transport site enables a stationary proton gradient to facilitate the conversion of zinc-binding energy to the kinetic power stroke of a vectorial zinc transport (Gupta et al. 2014). Of the two cavities of the dimer, only one was accessible from the cytosol during transport. Zinc(II) binding to D49 of the transport site triggered a rearrangement of the TMS that closed the accessible cavity. The free-energy profiles of metal transit in the channel suggested the existence of a high barrier preventing release from the transport site (Sala et al. 2019). The mechanism of zinc transport through YiiP has been proposed (Sharma and Merz 2022).

Bacteria

YiiP of E. coli (P69380)

Cobalt/zinc resistance protein B, CzrB, of 291 aas and 6 TMSs.  It has a cytosolic extramembranal C-terminus. This 92-residue fragment may function independently of the full-length integral membrane protein. X-ray analyses of this fragment to 2.2 A resolution with and 1.7 A without zinc ions have been solved. The former has at least two zinc ions bound per monomer (Höfer et al. 2007).  Full-length variants of CzrB in the apo and zinc-loaded states were generated by homology modeling with the Zn²⁺/H⁺ antiporter YiiP. The model suggests a way in which zinc binding to the cytoplasmic fragment creates a docking site to which a metallochaperone can bind for delivery and transport of zinc. A proposal was advanced that it functions as a metallochaperone and regulates the zinc-transporting activity of the full-length protein. The latter requires that zinc binding becomes uncoupled from the creation of a metallochaperone-docking site on CzrB (Cherezov et al. 2008).

CzrB of Thermus thermophilus

Magnetosome protein, MamV, of 322 aas and 5 TMSs.  Putative Co/Zn/Cd cation transporter (Smalley et al. 2015).

MamV of Magnetospirillum magnetotacticum MS-1

Magnetosome membrane iron transporter, MamB.  Forms a heterodimeric stable complex with MamM which stabilizes MamB.  MamB also interacts with other proteins including the PDZ1 domain of MamE (Q6NE61).  Both MamB and MamM are essential for magnetite biomineralization and are involved in several steps in magnetosome formation. MamM was used to probe the role of the hydrophilic C-terminal domain (CTD) in metal recognition and selectivity. Different metals bind to MamM CTD, suggesting a varying level of functional discrimination between CDF domains. Thus, CDF CTDs play a role in metal selectivity. MamM's CTD discriminates against Mn²⁺, supporting a role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn²⁺ incorporation (Barber-Zucker et al. 2020).

Bacteria

MamB of Magnetospirillum gryphiswaldense

Putative magnetosome membrane iron transporter, MamM.  Forms a heterodimeric stable complex with MamB which it stabilizes.  MamB (see TC# 2.A.4.7.3) also interacts with other proteins including the PDZ1 domain of MamE (Q6NE61).  Both MamB and MamM are essential for magnetite biomineralization and are involved in several steps in magnetosome formation, but only MamB is essential for formation of magnetosome membrane vesicles (Uebe et al. 2011). Most CDF proteins contain two domains, the cation transporting transmembrane domain and the regulatory cytoplasmic C-terminal domain (CTD). A MamM M250P mutation that is synonymous with the disease-related mutation L349P of the human CDF protein, ZnT-10 causes severe structural changes in its CTD, resulting in abnormally reduced function.Thus, the CTD fold is critical for the CDF proteins' proper function and suggest that the CDF cytoplasmic domain is a CDF regulatory element (Barber-Zucker et al. 2016). MamM's CTD can discriminate against Mn²⁺, supporting its postulated role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn²⁺ incorporation (Barber-Zucker et al. 2020).

Bacteria

MamM of Magnetospirillum gryphiswaldense

Cd²⁺/Zn²⁺ efflux pump, YiiP or FieF. A low resolution structure in the open configuration has been determined by cryoelectron microscopy (Coudray et al. 2013).

Proteobacteria

YiiP of Shewanella oneidensis (Q8E919)

Dimeric Mn²⁺ efflux transporter, MntE of 394 aas (Rosch et al. 2009; Lisher et al. 2013; Jakubovics and Valentine 2009; Martin and Giedroc 2016).

Firmicutes

MntE of Streptococcus pneumoniae

Mn²⁺ efflux pump, YiiP, probably a Mn²⁺:H⁺ antiporter.  Necessary for efficient nodulation of alfalfa plants (Raimunda and Elso-Berberián 2014)

Proteobacteria

YiiP of Sinorhizobium meliloti

CDF protein, exporting Zn²⁺ and Cd²⁺ (323 aas). It lacks the C-terminal hydrophilic domain (CTD) common to many CDF homologues (Kolaj-Robin et al. 2015).

Proteobacteria

CDF homologue of Maricaulis maris

Ferrous iron detoxifying protein, FieF, of 337 aas and 6 TMSs.  Also probably exports Zn²⁺, Co²⁺, Cd²⁺ and Ni²⁺ (Munkelt et al. 2004).

FieF of Cupriavidus metallidurans (Ralstonia metallidurans)

CDF Family homologue with MMT1 domain

Actinobacteria

CDF porter of Streptomyces coelicolor

CDF Family member

Actinobacteria

CDF cation efflux carrier of Mycobacterium tuberculosis

Zn²⁺ transporter, TMEM163 or Znt11, of 289 aas and 6 TMSs.  It interacts with TrpML1 (TC# 1.A.5.3.1), but by itself, it can pump out Zn²⁺ (Sanchez et al. 2019).  It may be involved in the human lipid storage disorder, mucolipidosis type IV (MLIV), caused by Zn²⁺ overload (Cuajungco et al. 2014). TMEM163 is found in synaptic vesicles where it is called SV31 (Burré et al. 2007). It plays a role in Zn²⁺ uptake into lysosomes (Cuajungco and Kiselyov 2017). TMEM163 proteins catalyze Zn²⁺ efflux from cells and are critical for the biogenesis of platelet dense granules in mice (Yuan et al. 2021). TMEM163's discovery, transport feature, protein interactome, and similarities, as well as differences, with known SLC30 (ZnT) protein family members have been reviewed (Styrpejko and Cuajungco 2021). These authors also examined recent reports that implicate TMEM163 directly or indirectly in various human diseases such as Parkinson's disease, Mucolipidosis type IV and diabetes. TMEM163 is a dimer that catalyzes Zn²⁺ efflux from cells, or uptake into intracellular vesicles including lysosomes. TMEM163 dimerizes with itself, but it also heterodimerizes with ZNT1, ZNT2, ZNT3, and ZNT4 proteins (Escobar et al. 2022).

Animals

TMEM163 of Homo sapiens