2.A.55 The Metal Ion (Mn2+-iron) Transporter (Nramp) Family
Homologues of this family are found in various yeasts, plants, animals, archaea, and Gram-negative and Gram-positive bacteria termed ''natural resistance-associated'' macrophage protein (NRAMP) proteins because one of the animal homologues plays a role in resistance to intracellular bacterial pathogens such as Salmonella enterica serovar Typhimurium, Leishmania donovani and Mycobacterium bovis. The natural history of SLC11 genes in vertebrates has been discussed by Neves et al. (2011). Proposed to be a distant member of the DMT Superfamily (TC# 2.A.7), several human pathologies may result from defects in Nramp-dependent
Fe2+ or Mn2+ transport, including iron overload, neurodegenerative diseases and innate
susceptibility to infectious diseases (Cellier 2012).
Humans and rodents possess two distinct NRAMPs. The broad specificity NRAMP2 (DMT1), which transports a range of divalent metal cations, transports Fe2+ and H+ with a 1:1 stoichiometry and apparent affinities of 6 μm and about 1 μm, respectively. Variable H+:Fe2+ stoichiometry has also been reported. The order of substrate preference for NRAMP2 is Fe2+> Zn2+> Mn2+> Co2+> Ca2+> Cu2+> Ni2+> Pb2+. Many of these ions can inhibit iron absorption. Mutation of Nramp2 in rodents leads to defective endosomal iron export within the ferritin cycle, impaired intestinal iron absorption and microcytic anemia. Symptoms of Mn2+ deficiency are also seen. It is found in apical membranes of intestinal epithelial cells but also in late endosomes and lysosomes.
In contrast to the widely expressed NRAMP2, NRAMP1 is expressed primarily in macrophages and monocytes and appears to have a preference for Mn2+ rather than Fe2+. NRAMP1 (TC# 2.A.55.2.3) has been reported to function by metal:H+ antiport (Techau et al., 2007). It is hypothesized that a deficiency for Mn2+ or some other metal prevents the generation of reactive oxygenic and nitrogenic compounds that are used by macrophage to combat pathogens. This hypothesis is supported by studies on the bacterial NRAMP homologues which exhibit extremely high selectivity for Mn2+ over Fe2+, Zn2+ and other divalent cations. Regulation of these transporters in bacteria can occur through Fur, OxyR, and most commonly a DtxR homolog, MntR.
The Smf1 protein of Saccharomyces cerevisiae appears to catalyze high-affinity (Km = 0.3 μm) Mn2+ uptake while the closely related Smf2 protein may catalyze low affinity (Km = 60 μm) Mn2+ uptake in the same organism. Both proteins also mediate H+-dependent Fe2+ uptake. These proteins are of 575 and 549 amino acyl residues in length and are predicted to have 8-12 transmembrane α-helical spanners. The E. coli homologue of 412 aas exhibits 11 putative and confirmed TMSs with the N-terminus in and the C-terminus out. The yeast proteins may be localized to the vacuole and/or the plasma membrane of the yeast cell. Indirect and some direct experiments suggest that they may be able to transport several heavy metals including Mn2+, Cu2+, Cd2+ and Co2+. A third yeast protein, Smf3p, appears to be exclusively intracellular, possibly in the Golgi. Nramp2 (Slc11A2) of Homo sapiens (TC #2.A.55.2.1) has a 12 TMS topology with intracellular N- and C-termini. Two-fold structural symmetry in the arrangement of membrane helices for TM1-5 and TM6-10 (conserved Slc2 hydrophobic core) is suggested (Czachorowski et al., 2009).
The Nramp family of divalent metal transporters enables manganese import
in bacteria and dietary iron uptake in mammals. Bozzi et al. 2016 determined the
crystal structure of the Deinococcus radiodurans Nramp homolog
(DraNramp) in an inward-facing apo state, including the complete
transmembrane (TM) segment 1a (absent from a previous Nramp structure). Cysteine accessibility scanning results Allowed identification of the metal-permeation pathway in the alternate
outward-open conformation. Two
natural anemia-causing glycine-to-arginine mutations impaired
transition metal transport in both human Nramp2 and DraNramp. The TM4
G153R mutation perturbs the closing of the outward metal-permeation
pathway and alters the selectivity of the conserved metal-binding site.
In contrast, the TM1a G45R mutation prevents conformational change by
sterically blocking the essential movement of that helix, thus locking
the transporter in an inward-facing state (Bozzi et al. 2016).
The generalized transport reaction catalyzed by Nramp family proteins is:
Me2+ (out) H+ (out) ⇌ Me2+ (in) H+ (in)
This family belongs to the APC Superfamily.
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|Mani, A. and K. Sankaranarayanan. (2018). In Silico Analysis of Natural Resistance-Associated Macrophage Protein (NRAMP) Family of Transporters in Rice. Protein J 37: 237-247.|
|Mizuno, T., K. Usui, K. Horie, S. Nosaka, N. Mizuno, and H. Obata. (2005). Cloning of three ZIP/Nramp transporter genes from a Ni hyperaccumulator plant Thlaspi japonicum and their Ni2+-transport abilities. Plant Physiol. Biochem 43: 793-801.|
|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.|
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|Nevo, Y. (2007). Site-directed mutagenesis investigation of coupling properties of metal ion transport by DCT1. Biochim. Biophys. Acta. 1778(1):334-341.|
|Patzer, S.I. and K. Hantke. (2001). Dua1 repression by Fe2+-Fur and Mn2+-MntR of the mntH gene, encoding an NRAMP-like Mn2+ transporter in Escherichia coli. J. Bacteriol. 183: 4806-4813.|
|Peracino, B., C. Wagner, A. Balest, A. Balbo, B. Pergolizzi, A.A. Noegel, M. Steinert, and S. Bozzaro. (2006). Function and mechanism of action of Dictyostelium Nramp1 (Slc11a1) in bacterial infection. Traffic 7: 22-38.|
|Peracino, B., S. Buracco, and S. Bozzaro. (2013). The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum. J Cell Sci 126: 301-311.|
|Picard, V., G. Govoni, N. Jabado, and P. Gros. (2000). Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. J. Biol. Chem. 275: 35738-35745.|
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|Portnoy, M.E., X.F. Liu, and V.C. Culotta. (2000). Saccharomyces cerevisiae expresses three functionally distinct homologues of the NRAMP family of metal transporters. Mol. Cell Biol. 20: 7893-7902. |
|Que, Q. and J.D. Helmann. (2000). Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional regulator related to the diphtheria toxin repressor family of proteins. Mol. Microbiol. 35: 1454-1468. |
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High-affinity Me2+ (Fe2+, Mn2+, Zn2+, Cu2+, Cd2+, Ni2+, Co2+) uptake transporter, Smf1p or ESP1p of 575 aas and 11 TMSs. Important for oxidative stress protection. Its activity is regulated by the Tre1 protein alone, and it's degradation is dependent on the Bsd2, Rsp5, Tre1 and Tre2 proteins (Stimpson et al. 2006).
Eukaryotes, bacteria, archaea
Smf1p of Saccharomyces cerevisiae
Low-affinity Me2+ (Mn2+, Cu2+) uptake transporter, Smf2p. Essential for manganese uptake.
Eukaryotes, bacteria, archaea
Smf2p of Saccharomyces cerevisiae
|2.A.55.1.3||Intracellular (Golgi?) heavy metal transporter, Smf3p ||Yeast ||Smf3p of Saccharomyces cerevisiae (NP_013134)|
Manganese transporter Pdt1
Pdt1 of Schizosaccharomyces pombe
Plasma membrane NRAMP divalent cation (Fe2+ and Cd2+ demonstrated) uptake system of 571 aas and 11 TMSs. Cd2+ down regluates expression (Wei et al. 2015).
NRAMP of Exophiala pisciphila
Heavy metal (Fe2+, Zn2+, Mn2+, Cu2+, Cd2+, Co2+, Ni2+ and Pb2+) ion:H+ symporter, Nramp2 or divalent metal transporter, DMT1 (Garrick et al. 2003). A 12 TMS topology with intracellular N- and C- termini is established. Two-fold structural symmetry in the arrangement of membrane helices for TM1-5 and TM6-10 (conserved Slc11 hydrophobic core) is suggested (Czachorowski et al., 2009). A conserved motif in a central flexible region of TMS1 (DPGN) binds the metal ion (Wang et al. 2011). Upregulated by iron deficiency and downregulated by iron loading (Nam et al. 2013). NRAMP2 also serves as the Sindbis alpha virus receptor (Rose et al. 2011). DMT1 interacts with the iron chaparone protein, PCBP2 (Q15366), in an iron-dependent fashion, and may be essential for iron uptake (Lane and Richardson 2014). Mutations cause a syndrome of congenital microcytic hypochromic anemia, poorly responsive to oral iron treatment, with liver iron overload associated paradoxically with normal to moderately elevated serum ferritin levels (Beaumont et al. 2006). Nigral iron accumulation and activation of NMDA receptors (NRs) contribute to the neurodegeneration of dopamine (DA) neurons in Parkinson's disease (PD), and activation of NRs participates in iron metabolism in the hippocampus (Xu et al. 2018). NR inhibitors MK-801 and AP5 protect nigrostriatal projection systems and reduce nigral iron levels. NMDA treatment increased the expression of DMT1 and decreased the expression of the iron exporter ferroportin 1 (Fpn1) (TC# 2.A.100.1.4) (Xu et al. 2018).
DMT1 (SLC11A2) of Homo sapiens
NRAMP2 (SLC11a2) of 552 aas and 10 TMSs. Inovoled in iron hoemeostasis and infectivity together with NRAMP1 (TC#2.A.55.2.9). Present in the contractile vacuole which regulates osmolarity and possible stores iron (Peracino et al. 2013).
NRAMP2 of Dictyostelium discoideum
NRAMP2 of 596 aas and 12 TMSs. NRAMP2 also serves as the Sindbis alpha virus receptor (Rose et al. 2011).
NRAMP2 of Drosophila melanogaster
VO2+ (vanidate) NRAMP uptake system in vacuoles of vanadocytes (587 aas; Ueki et al. 2011).
Vanidate transporter of Ascidia sydneiensis samea (Vanadium-rich ascidian)
Enterocyte iron uptake system, NRAMP or DMT1 of 558 aas and 13 TMSs. Inhibited by lead and cadmium ions competitively (Kwong et al. 2010). The close (85% identity) homologue from Scophthalmus maximus (Turbot) (Psetta maxima) has been characterized (Chen et al. 2007).
DMT1 of Oncorhynchus mykiss (Rainbow trout) (Salmo gairdneri)
NRAMP3 iron/cadmium transporter of 512 aas (Wei et al. 2009).
NRAMP3 of Noccaea caerulescens
Divalent cation and aluminum transporter, Smf3. Mediates aluminum-induced dopamine neuron degeneration (VanDuyn et al. 2013).
Smf3 of Caenorhabditis elegans
Fe2+/Mn2+ transporter, Smf1 of 562 aas and 12 TMSs (Au et al. 2009).
Smf1 of Caenorhabditis elegans
DMT1, SLC11A2 or NRAMP2, isoform 1, of 564 aas and 12 TMSs. It is an electrogenic Mn2+ transporter that is expressed
at high levels in the brush-border membranes of enterocytes (Bai et al. 2008).
DMT1 of Gallus gallus (chicken)
NRAMP4 of 512 aas and 12 TMSs, a vacuolar metal transporter involved in
intracellular metal homeostasis. It can transport iron (Fe), manganese (Mn)
and cadmium (Cd), and regulates metal accumulation under Fe starvation. It acts redundantly with NRAMP3 (which is 85% identical to it) to mobilize vacuolar Fe and provide
sufficient Fe during seed germination (Lanquar et al. 2005). In association with NRAMP3,
it is required for optimal growth and photosynthesis under Mn deficiency. It exports Mn from vacuoles in leaf mesophyll cells, making Mn available
for functional photosystem II in chloroplasts (Lanquar et al. 2010). Its ortholog in Thlaspi japonicum has been characterized (Mizuno et al. 2005).
NRAMP4 of Arabidopsis thaliana
Me2+ (Fe2+, Cd2+, Co2+):H+ symporter, DCT1 (Nramp2) (Splice variant isoforms serve different functions). The stoichiometry between metal ion and proton in the symport process catalyzed by DCT1 varies under different conditions due to mechanistic proton slip. A single reciprocal mutation, I144F, in TMS2 of DCT1 abolished the metal ion transport activity, increased the slip currents, and generated sodium slip currents (Nevo, 2007). A double mutation, adding F227I in TMS4 to I144F restored the uptake activity of DCT1 and reduced the slip currents. Thus, these regions are important in coupling metal ion and proton symport (Nevo, 2007). NRAMP2 also serves as the Sindbis alpha virus receptor (Rose et al. 2011). Three isoforms are expressed differentially in different cell types and are developmentally regulated (Ding et al. 2013).
DCT1 of Rattus norvegicus
Macrophage divalent cation (Mn2+ > Fe2+):H+ antiporter (catalyzes divalent cation efflux and regulates cation homeostasis), NRAMP1 or Slc11a2. (Techau et al., 2007). The G212V mutation leads to microcytic anemia and liver iron overload (Bardou-Jacquet et al., 2011). Multiple targeting motifs direct NRAMP1 into lysosomes (Cheng and Wang, 2012). The structure and topology has been studied revealing a symmetric but inversely oriented arrangement (Li et al., 2012).
|Animals||SLC11A1 of Homo sapiens|
The major root plasma membrane high affinity Me2+(Fe2+ Co2+ Mn2+) uptake transporter, NRAMP-1 (stimulated by Mn2+ deficiency) (Cailliatte et al., 2010). In silico analyses of plant NRAMPs have been performed using NRAMP1 as the query sequence (Vatansever et al. 2016).
NRAMP-1 of Arabidopsis thaliana (Q9SAH8)
Nramp aluminum transporter 1, Nrat1; specific for trivalent Al ion in rice (Xia et al., 2010; Xia et al. 2011). There are 7 isoforms of NRAMPs in rice, and they transport a variety of metals, Zn2+, Mn2+, Fe2+, Cd2+, etc. (Mani and Sankaranarayanan 2018).
Nrat1 of Oryza sativa (Q6ZG85)
Mn2+ transporter, MntH (Hohle and O'Brian, 2009)
MntH of Bradyrhizobium japonicum (Q89K67)
Iron transporter, NRAMP isoform III (Lin et al., 2011).
NRAMP isoform III of Perkinsus marinus (D5FGJ2)
|2.A.55.2.8||Ethylene-insensitive protein 2 (AtEIN2) (EIN-2) (Cytokinin-resistant protein AtCKR1)||Plants||EIN2 of Arabidopsis thaliana |
NRAMP1 (SLC11a1) of 533 aas and 11 TMSs. Regulates iron homeostasis and bacterial infection; present in phagosomes and macroinosomes (Peracino et al. 2013). Transports metal cations out of the phagolysosome, thereby depleting iron. Nramp1 overexpression
protects cells from L. pneumophila infection (Peracino et al. 2006).
NRAMP1 of Dictyostelium discoideum
Me2+ (Mn2+, Fe2+, Cd2+, Co2+, Zn2+, Ni2+):H+ symporter, MntH (Mn2+ · MntR and Fe2+ · Fur repressible). Specific resides in TMS1 and 6 line the pore and play a role in pH regulation (Courville et al., 2004; Haemig et al. 2010). Important for virulence in Salmonella (Karlinsey et al., 2010).
MntH (YfeP) of E. coli (P0A769)
|2.A.55.3.2||MntH homologue (20% I) of unknown function||Bacteria||YcsG of Bacillus subtilis (P42964)|
|2.A.55.3.3||Manganese transport protein MntH||Bacilli||MntH of Bacillus subtilis |
Putative metal ion transport protein
Putative metal ion transport protein of Streptomyces coelicolor
Uncharacterized permease of 406 aas
UP of Pseudomonas stutzeri
NRAMP homologue; putative manganese porter of 544 aas and 13 TMSs.
Mn2+ porter of Bradyrhizobium sp.
H+-stimulated, divalent metal cation uptake system, MntH of 436 aas and 11 TMSs. The x-ray structure has been determined, revealing the probable ion translocation pathway (Bozzi et al. 2016).
MntH of Deinococcus radiodurans
Uncharacterized protein of 465 aas and 11 TMSs (Hug et al. 2016).
UP of Candidatus Peribacter riflensis
NRAMP homologue of 483 aas and 11 TMSs in a 6 + 5 TMS arrangement.
NRAMP homologue of Saccharopolyspora erythraea