Magnesium transporters

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The evolution of Mg²⁺ transport appears to have been rather complicated. Proteins apparently based on MgtE are present in bacteria and metazoa, but are missing from fungi and plants, whilst proteins apparently related to CorA are present in all of these groups. The two active-transport transporters present in bacteria, MgtA and MgtB, do not appear to have any homologues in the higher organisms. There are also Mg²⁺ transport systems that are found only in the higher organisms.

Clearly there are a large number of proteins yet to be identified that transport Mg²⁺. Even in the best studied eukaryote, yeast, Borrellycite journal| last=Borrelly| first= G. | coauthors=Boyer, J.-C., Touraine, B., Szponarski, W., Rambier, M., and Gibrat, R. | year= 2001| title= The yeast mutant vps5D affected in the recycling of Golgi membrane proteins displays an enhanced vacuolar Mg²⁺/H⁺ exchange activity| journal=PNAS| volume= 98| pages=9660–9665| doi=10.1073/pnas.161215198| pmid=11493679] have reported a Mg²⁺/H⁺ exchanger, without an associated protein, which is probably localised to the Golgi. At least one other major Mg²⁺ transporter in yeast still unaccounted for — that effecting Mg²⁺ transport into and out of the yeast vacuole. In higher, multicellular organisms it seems that many Mg²⁺ transporting proteins await discovery.

The CorA-domain-containing Mg²⁺ transporters (CorA, Alr-like and Mrs2-like) have a similar but not identical array of affinities for divalent cations. In fact, this observation can be extended to all of the Mg²⁺ transporters so far identified. This similarity suggests that the basic properties of Mg²⁺ strongly influence the possible mechanisms of recognition and transport. However, this observation also suggests that using other metal ions as tracers for Mg²⁺ uptake will not necessarily produce results comparable to the transporter’s ability to transport Mg²⁺. Ideally, Mg²⁺ should be measured directlycite journal| last=Tevelev| first= A. | coauthors=Cowan, J.A.|year=1995| title= Metal substitution as a probe of the biological chemistry of magnesium ion. In The Biological Chemistry of Magnesium, J.A. Cowan, ed (New York: VCH)] .

In a world where ²⁸Mg²⁺ is practically unobtainable, much of the old data will need to be reinterpreted in terms of new tools for measuring Mg²⁺ transport, if different transporters are to be compared directly. The pioneering work of Kolisekcite journal| last=Kolisek| first= M. | coauthors=Zsurka, G., Samaj, J., Weghuber, J., Schweyen, R.J., and Schweigel, M.|year=2003| title= Mrs2p is an essential component of the major electrophoretic Mg²⁺ influx system in mitochondria| journal=EMBO Journal| volume= 22| pages=1235–1244| doi=10.1093/emboj/cdg122] and Froschauercite journal| last=Froschauer| first= E.M. | coauthors=Kolisek, M., Dieterich, F., Schweigel, M., and Schweyen, R.J.|year=2004| title= Fluorescence measurements of free [Mg²⁺] by use of mag-fura 2 in Salmonella enterica| journal=FEMS Microbiology Letters| volume= 237| pages=49–55] using mag-fura 2 has shown that free Mg²⁺ can be reliably measured "in vivo" in some systems. By returning to the analysis of CorA with this new tool, we have gained an important baseline for the analysis of new Mg²⁺ transport systems as they are discovered. However, it is important that the amount of transporter present in the membrane is accurately determined if comparisons of transport capability are to be made. This bacterial system might also be able to provide some utility for the analysis of eukaryotic Mg²⁺ transport proteins. However, the differences in biological systems between prokaryotes and eukaryotes will have to be considered as part of any experiment.

Comparing the functions of the characterised Mg²⁺ transport proteins is currently almost impossible. The proteins have been investigated in different biological systems using different methodologies and technologies. Finding a system where all the proteins can be compared directly would be a major advance. If the proteins could be shown to be functional in bacteria ("S. typhimurium") then a combination of the techniques of mag-fura 2, quantification of protein in the envelope membrane, and structure of the proteins (X-ray crystal or cryo-TEM) might allow the determination of the basic mechanisms involved in the recognition and transport of the Mg²⁺ ion. However, perhaps the best advance would be the development of methods allowing the measurement of the protein’s function in the patch-clamp system using artificial membranes.

Bacteria

Early research

CorA

The CorA gene and its corresponding protein are the most exhaustively studied Mg²⁺ transport system in any organism. Most of the published literature on the CorA gene comes from the laboratory of M. E. Maguire. Recently the group of R. J. Schweyen has made a significant impact on the understanding Mg²⁺ transport by CorA. The gene was originally named after the cobalt-resistant phenotype in "E. coli" that was caused by the gene’s inactivation.

The gene was genetically identified in "E. coli" by Park "et al.", but wasn’t cloned until Hmiel "et al." isolated the "Salmonella enterica" serovar Typhimurium ("S. typhimurium") homologue. Later it would be shown by Smith and Maguirecite journal| last=Smith| first= R.L. | coauthors=Maguire, M.E.|year=1995a| title= Distribution of the CorA Mg²⁺ transport system in gram-negative bacteria| journal=Journal of Bacteriology | volume=177| pages=1638–1640] that the CorA gene was present in 17 gram-negative bacteria. With the large number of complete genome sequences now available for the prokaryotes, CorA has been shown to be virtually ubiquitous amongst the Eubacteria, as well as being widely distributed within the Archaeacite journal| last=Kehres| first= D.G. | coauthors=Lawyer, C.H., and Maguire, M.E.|year=1998| title= The CorA magnesium transporter gene family| journal=Microbial and Comparative Genomics| volume= 3| pages=151–169] . The CorA locus in "E. coli" contains a single open reading frame of 948 nucleotides, producing a protein 316 amino acids in size. This protein is well conserved amongst the Eubacteria and Archaea. Between "E. coli" and "S. typhimurium" the proteins are 98% identical, but in more distantly related species the similarity falls to between 15 and 20%. In the more distantly related genes the similarity is often restricted to the C-terminal part of the protein, and a short amino acid motif GMN within this region is very highly conserved. The CorA domain, also known as PF01544 in the pFAM conserved protein domain database (www.sanger.ac.uk/Software/Pfam/), is additionally present in a wide range of higher organisms and these transporters will be reviewed below.

The CorA gene is constitutively expressed in "S. typhimurium" under a wide range of external Mg²⁺ concentrationscite journal| last=Snavely| first= M.D. | coauthors=Gravina, S.A., Cheung, T.T., Miller, C.G., and Maguire, M.E.|year=1991a| title= Magnesium transport in "Salmonella typhimurium". Regulation of mgtA and mgtB expression| journal=Journal of Biological Chemistry | volume=266| pages=824–829] . However, recent evidence suggests that the activity of the protein may be regulated by the PhoPQ two-component regulatory systemcite journal| last=Chamnongpol| first= S. | coauthors=Groisman, E.A. | year=2002| title= Mg²⁺ homeostasis and avoidance of metal toxicity| journal=Molecular Microbiology| volume= 44| pages=561–571| doi=10.1046/j.1365-2958.2002.02917.x] . This sensor responds to low external Mg²⁺ during the infection process of "S. typhimurium" in humanscite journal| last=Groisman| first= E.A.|year=2001| title= The pleiotropic two-component regulatory system PhoP-PhoQ| journal=Journal of Bacteriology | volume=183| pages=1835–1842| doi= 10.1128/JB.183.6.1835-1842.2001| pmid=11222580] . In low external Mg²⁺ conditions the PhoPQ system was reported to suppress the function of CorA and it has been previously shown that the transcription of the alternative Mg²⁺ transporters MgtA and MgtB is activated in these conditions. Chamnongpol and Groisman suggest that this allows the bacteria to escape metal ion toxicity caused by the transport of other ions, particularly Fe(II), by CorA in the absence of Mg²⁺. For a conflicting report on the source of toxicity, see Papp and Maguirecite journal| last=Papp| first= K.M. | coauthors=Maguire, M.E.|year=2004| title= The CorA Mg²⁺ transporter does not transport Fe²⁺| journal=Journal of Bacteriology | volume=186| pages=7653–7658| doi=10.1128/JB.186.22.7653-7658.2004| pmid=15516579] .

The figure (not to scale) shows the originally published transmembrane (TM) domain topology of the "S. typhimurium" CorA protein, which was said to have three membrane-spanning regions in the C-terminal part of the protein (shown in blue), as determined by Smith "et al."cite journal| last=Smith| first= R.L. | coauthors=Banks, J.L., Snavely, M.D., and Maguire, M.E.|year=1993a| title= Sequence and topology of the CorA magnesium transport systems of Salmonella typhimurium and Escherichia coli: Identification of a new class of transport protein| journal=Journal of Biological Chemistry | volume=268| pages=14071–14080] . Evidence for CorA acting as a homotetramer was published by Warren "et al." in 2004cite journal| last=Warren| first= M.A. | coauthors=Kucharski, L.M., Veenstra, A., Shi, L., Grulich, P.F., and Maguire, M.E.|year=2004| title= The CorA Mg²⁺ transporter is a homotetramer| journal=Journal of Bacteriology | volume=186| pages=4605–4612| doi=10.1128/JB.186.14.4605-4612.2004| pmid=15231793] . In December 2005 the crystal structure of the CorA channel was posted to the RSCB protein structure database. The results show that the protein has two TM domains and exists as a homopentamer, in direct conflict with the eariler reports. [http://www.rcsb.org/pdb/navbarsearch.do?newSearch=yes&isAuthorSearch=no&radioset=Structures&inputQuickSearch=2bbj&image.x=0&image.y=0&
] . The soluble intracellular parts of the protein are highly charged containing 31 positively charged and 53 negatively charged residues. Conversely, the TM domains contain only one charged amino acid , which has been shown to be unimportant in the activity of the transportercite journal| last=Smith| first= R.L. | coauthors=Szegedy, M.A., Kucharski, L.M., Walker, C., Wiet, R.M., Redpath, A., Kaczmarek, M.T., and Maguire, M.E.|year=1998a| title= The CorA Mg²⁺ transport protein of Salmonella typhimurium: Mutagenesis of conserved residues in the third membrane domain identifies a Mg²⁺ pore| journal=Journal of Biological Chemistry | volume=273| pages=28663–28669| doi=10.1074/jbc.273.44.28663| pmid=9786860] . From mutagenesis experiments it appears that the chemistry of Mg²⁺ transport relies on hydroxyl groups lining the inside of the transport pore; there is also an absolute requirement for the GMN motif (shown in red)cite journal| last=Szegedy| first= M.A. | coauthors=Maguire, M.E.|year=1999| title= The CorA Mg²⁺ transport protein of Salmonella typhimurium. Mutatgenesis of conserved residues in the second transmembrane domain| journal=Journal of Biological Chemistry | volume=274| pages=36973–36979| doi=10.1074/jbc.274.52.36973| pmid=10601252] .

Before the activity of CorA could be studied "in vivo", any other Mg²⁺ transport systems in the bacterial host had to be identified and inactivated/deleted (see below). A strain of "S. typhimurium" containing a functional CorA gene but lacking MgtA and MgtB was constructedcite journal| last=Hmiel| first= S.P. | coauthors=Snavely, M.D., Florer, J.B., Maguire, M.E., and Miller, C.G.|year=1989| title= Magnesium transport in Salmonella typhimurium: genetic characterization and cloning of three magnesium transport loci| journal=Journal of Bacteriology| volume= 171| pages=4742–4751] (see also below), and the uptake kinetics of the transporter were analysedcite journal| last=Snavely| first= M.D. | coauthors=Florer, J.B., Miller, C.G., and Maguire, M.E.|year=1989b| title= Magnesium transport in Salmonella typhimurium: ^{28/sup>Mg²⁺ transport by the CorA, MgtA, and MgtB systems| journal=Journal of Bacteriology | volume=171| pages=4761–4766}] . This strain showed nearly normal growth rates on standard media (50 μM Mg²⁺), but the removal of all three genes created a bacterial strain requiring 100 mM external Mg²⁺ for normal growth.

Mg²⁺ is taken up into cells containing only the CorA transport system with similar kinetics and cation sensitivities as the Mg²⁺ uptake described in the earlier papers, and has additionally been quantified(see table). The uptake of Mg²⁺ was seen to plateau as in earlier studies, and although no actual mechanism for the decrease in transport has been determined, it has been assumed that the protein is inactivated. Co²⁺ and Ni²⁺ are toxic to "S. typhimurium" cells containing a functional CorA protein and this toxicity stems from the blocking of Mg²⁺ uptake (competitive inhibition) and the accumulation of these ions inside the cell. Co²⁺ and Ni²⁺ have been shown to be transported by CorA by using radioactive tracer analysiscite journal| last=Gibson| first= M.M. | coauthors=Bagga, D.A., Miller, C.G., and Maguire, M.E.|year=1991| title= Magnesium transport in Salmonella typhimurium: the influence of new mutations conferring Co²⁺ resistance on the CorA Mg²⁺ transport system| journal=Molecular Microbiology| volume= 5| pages=2753–2762| doi=10.1111/j.1365-2958.1991.tb01984.x] , although with lower affinities (Km) and velocities (Vmax) than for Mg²⁺ (see table). The Km values for Co²⁺ and Ni²⁺ are significantly above those expected to be encountered by the cells in their normal environment, so it is unlikely that the CorA transport system mediates the uptake of these ions under natural conditions. To date, the evidence for Mn²⁺ transport by CorA is limited to "E. coli".

The table shows a comparison of transport kinetics of MgtE and CorA. Key kinetic parameter values for MgtE and CorA are listed. As shown, the data has been generated at differing incubation temperatures. Km and Ki are not significantly altered by the differing incubation temperature. Conversely, Vmax shows a strong positive correlation with temperature, hence the value of Co²⁺ Vmax for MgtE is not directly comparable with the values for CorA.

Yeast

Early research

The earliest research showing that yeast take up Mg²⁺ appears to be Schmidt "et al." (1949). However, these authors only showed altered yeast Mg²⁺ content in a table within the paper, and the report’s conclusions dealt entirely with the metabolism of phosphate. A series of experiments by Rothsteincite journal| last=Rothstein| first= A., Hayes| coauthors=A., Jennings, D., and Hooper, D.|year=1958| title= The active transport of Mg²⁺ and Mn²⁺ into the yeast cell| journal=Journal of General Physiology | volume=41| pages=585–594| doi=10.1085/jgp.41.3.585| pmid=13491823] cite journal| last=Fuhrmann| first= G.-F. | coauthors=Rothstein, A.|year=1968| title= The transport of Zn²⁺, Co²⁺ and Ni²⁺ into yeast cells| journal=Biochimica et Biophysica Acta | volume=163| pages=325–330| doi=10.1016/0005-2736(68)90117-X] shifted the focus more towards the uptake of the metal cations, showing that yeast take up cations with the following affinity series: Mg²⁺, Co²⁺, Zn²⁺ > Mn²⁺ > Ni²⁺ > Ca²⁺ > Sr²⁺. Additionally, it was suggested that the transport of the different cations is mediated by the same transport systemcite journal| last=Norris| first= P.R. | coauthors=Kelly, D.P.|year=1977| title= Accumulation of cadmium and cobalt by Saccharomyces cerevisiae| journal=Journal of General Microbiology | volume=99| pages=317–324] cite journal| last=Okorokov| first= L.A. | coauthors=Lichko, L.P., Kadomtseva, M., Kholodenko, V.P., Titovsky, V.T., and Kulaev, I.S.|year=1977| title= Energy-dependent transport of manganese into yeast cells and distribtuion of accumulated ions| journal=European Journal of Biochemistry| volume= 75| pages=373–377| doi= 10.1111/j.1432-1033.1977.tb11538.x] cite journal| last=Conklin| first= D.S. | coauthors=Kung, C., and Culbertson, M.R.|year=1993| title= The COT2 gene is required for glucose-dependent divalent cation transport in Saccharomyces cerevisiae| journal=Molecular and Cellular Biology | volume=13| pages=2041–2049] — a situation very much like that in bacteria.

In 1998, MacDiarmid and Gardner finally identified the proteins responsible for the observed cation transport phenotype in "Saccharomyces cerevisiae". The genes involved in this system and a second mitochondrial Mg²⁺ transport system, functionally identified significantly after the gene was cloned, are described in the sections below.

ALR1 and ALR2

Two genes, ALR1 and ALR2, were isolated in a screen for Al³⁺ tolerance (resistance) in yeast. Overexpression constructs containing yeast genomic DNA were introduced into wild type yeast and the transformants screened for growth on toxic levels of Al³⁺. ALR1 and ALR2 containing plasmids allowed the growth of yeast in these conditions.

The Alr1p and Alr2p proteins consist of 859 and 858 amino acids respectively, and are 70% identical. A region in the C-terminal half of these proteins is weakly similar to the full CorA protein. The computer-predicted TM topology of Alr1p is shown in the figure. The presence of a third TM domain was suggested by MacDiarmid and Gardner (1998) on the strength on sequence homology and more recently by Lee and Gardner (2006)cite journal |author=Lee J, Gardner R |title=Residues of the yeast ALR1 protein that are critical for magnesium uptake |journal=Curr Genet |volume=49 |issue=1 |pages=7–20 |year=2006 |pmid=16328501 |doi=10.1007/s00294-005-0037-y] , on the strength of mutagenesis studies, making the TM topology of these proteins more like that of CorA (see figure). Also of note is that Alr1p contains the conserved GMN motif at the outside end of TM 2 (TM 2') and that the mutation of the methionine (M) in this motif to a leucine (L) led to the loss of transport capability.

The figure shows the two possible TM topologies of Alr1p. Part A of the figure shows the computer-predicted membrane topology of the Alr1p protein in yeast. Part B shows the topology of Alr1p based on the experimental results of Lee and Gardner (2006). The GMN motif location is indicated in red and the TM domains in light blue. The orientation in the membrane and the positions of the N- and C-termini are indicated. The various sizes of the soluble domains are given in amino acids (AA). TM domains are numbered by their similarity to CorA. Where any TM domain is missing the remaining domains are numbered with primes. Not drawn to scale.A third ALR-like gene is present in "S. cerevisiae" and there are two homologous genes in both "Schizosaccharomyces pombe" and "Neurospora crassa". These proteins contain a GMN motif like that of CorA, with the exception of the second "N. crassa" gene. No ALR-like genes have been identified in species outside of the fungi.

Membrane fractionation and green fluorescent protein (GFP) fusion studies established that Alr1p is localised to the plasma membranecite journal| last=Graschopf| first= A. | coauthors=Stadler, J.A., Hoellerer, M.K., Eder, S., Sieghardt, M., Kohlwein, S.D., and Schweyen, R.J.|year=2001| title= The yeast plasma membrane protein Alr1 controls Mg²⁺ homeostasis and is subject to Mg²⁺-dependent control of its synthesis and degradation| journal=Journal of Biological Chemistry| volume= 276| pages=16216–16222| doi=10.1074/jbc.M101504200| pmid=11279208] . Interestingly, the localisation of the Alr1p was observed to be internalised and degraded in the vacuole in response to extracellular cations. Mg²⁺ at very low extracellular concentrations (100 μM; < 10% of the standard media Mg²⁺ content) and Co²⁺ and Mn²⁺ at relatively high concentrations (> 20× standard media) induced the change in Alr1p protein localisation and the effect was dependent on functional ubiquitination, endocytosis and vacuolar degradation. This mechanism allows a regulation of Mg²⁺ uptake by yeast. Whether this degradation is triggered by the binding of the ions to the transporter or by some less direct mechanism has not been determined.

A functional Alr1p (wild type) or Alr2p (overexpressed) is required for "S. cerevisiae" growth in standard conditions (4 mM Mg²⁺) and Alr1p can support normal growth at Mg²⁺ concentrations as low as 30 μM. ⁵⁷Co²⁺ is taken up into yeast via the Alr1p protein with a Km of 77 – 105 μM (; C. MacDiarmid and R. C. Gardner, unpublished data), but the Ki for Mg²⁺ inhibition of this transport is currently unknown. The transport of other cations by the Alr1p protein was assayed by the inhibition of yeast growth. The overexpression of Alr1p led to increased sensitivity to Ca²⁺, Co²⁺, Cu²⁺, La³⁺, Mn²⁺, Ni²⁺ and Zn²⁺, an array of cations similar to those shown to be transported into yeast by a CorA-like transport system. The increased toxicity of the cations in the presence of the transporter is assumed to be due to the increased accumulation of the cation inside the cell.

The evidence that Alr1p is primarily a Mg²⁺ transporter is that the loss of Alr1p leads to a decreased total cell content of Mg²⁺ but not of the other cations, and that the regulation of the transporter occurs at environmental concentrations of Mg²⁺, but not the other cations tested. Additionally, two electrophysiological studies where Alr1p was produced in yeast or "Xenopus" oocytes showed a Mg²⁺-dependent current in the presence of the proteincite journal| last=Liu| first= G.J. | coauthors=Martin, D.K., Gardner, R.C., and Ryan, P.R.|year=2002| title= Large Mg²⁺-dependent currents are associated with the increased expression of ALR1 in Saccharomyces cerevisiae| journal=FEMS Microbiology Letters | volume=213| pages=231–237| doi=10.1111/j.1574-6968.2002.tb11311.x] ; Salih "et al.", in prep.).

The kinetics of Mg²⁺ uptake by Alr1p have been investigated by electrophysiology techniques on whole yeast cells. The results suggested that Alr1p is very likely to act as an ion-selective channel. In the same paper the authors reported that Mg²⁺ transport by Alr1p varied from 200 pA to 1500 pA, with a mean current of 264 pA. No quantification of the amount of protein producing the current was presented, and so the results lack comparability with the bacterial Mg²⁺ transport proteins.

The alternative techniques of ²⁸Mg²⁺ radiotracer analysis and mag-fura 2 to measure Mg²⁺ uptake have not yet been used with Alr1p. ²⁸Mg²⁺ is currently not available and the mag-fura 2 system is unlikely to provide simple uptake data in yeast. The yeast cell maintains a heterogeneous distribution of Mg²⁺cite journal| last=Zhang| first= A. | coauthors=Cheng, T.P., Wu, X.Y., Altura, B.T., and Altura, B.M.|year=1997| title= Extracellular Mg²⁺ regulates intracellular Mg²⁺ and its subcellular compartmentation in fission yeast, Schizosaccharomyces pombe| journal=Cellular and Molecular Life Sciences | volume=53| pages=69–72| doi=10.1007/PL00000581] suggesting that multiple systems inside the yeast are transporting Mg²⁺ into storage compartments. This internal transport will very likely mask the uptake process. The expression of ALR1 in "S. typhimurium" without Mg²⁺ uptake genes may be an alternative, but as stated earlier, the effects of a heterologous expression system would need to be taken into account.

MRS2 and Lpe10

Like the ALR genes the MRS2 gene was cloned and sequenced before it was identified as a Mg²⁺ transporter. The MRS2 gene was identified in the nuclear genome of yeast in a screen for suppressors of a mitochondrial gene RNA splicing mutationcite journal| last=Koll| first= H. | coauthors=Schmidt, C., Wiesenberger, G., and Schmelzer, C.|year=1987| title= Three nuclear genes suppress a yeast mitochondrial splice defect when present in high copy number| journal=Current Genetics | volume=12| pages=503–510| doi= 10.1007/BF00419559] , and was cloned and sequenced by Wiesenberger "et al." (1992)cite journal| last=Wiesenberger| first= G. | coauthors=Waldherr, M., and Schweyen, R.J.|year=1992| title= The nuclear gene MRS2 is essential for the excision of group II introns from yeast mitochondrial transcripts "in vivo"| journal=Journal of Biological Chemistry | volume=267| pages=6963–6969] . Mrs2p was not identified as a putative Mg²⁺ transporter until Bui "et al." (1999). Gregan "et al." (2001a) identified LPE10 by homology to MRS2 and showed that both LPE10 and MRS2 mutants altered the Mg²⁺ content of yeast mitochondria and affected RNA splicing activity in the organellecite journal| last=Gregan| first= J. | coauthors=Bui, D.M., Pillich, R., Fink, M., Zsurka, G., and Schweyen, R.J.|year=2001a| title= The mitochondrial inner membrane protein Lpe10p, a homologue of Mrs2p, is essential for magnesium homeostasis and group II intron splicing in yeast| journal=Molecular Genome and Genetics | volume=264| pages=773–781] cite journal| last=Gregan| first= J. | coauthors=Kolisek, M., and Schweyen, R.J.|year=2001b| title= Mitochondrial Mg²⁺ homeostasis is critical for group II intron splicing "in vivo"| journal=Genes & Development | volume=15| pages=2229–2237| doi=10.1101/gad.201301] . Mg²⁺ transport has been shown to be directly mediated by Mrs2p, but not for Lpe10p.

The Mrs2p and Lpe10p proteins are 470 and 413 amino acid residues in size, respectively, and a 250 – 300 amino acid region in the middle of the proteins shows a weak similarity to the full CorA protein. The TM topologies of the Mrs2p and Lpe10p proteins have been assessed using a protease protection assay and are shown in the figure. TM 1 and 2 correspond to TM 2 and 3 in the CorA protein. Note the conserved GMN motif at the outside end of the first TM domain. When the glycine (G) in this motif was mutated to a cysteine (C) in Mrs2p, Mg²⁺ transport was strongly reduced.

The figure shows the experimentally determined topology of Mrs2p and Lpe10p as adapted from Bui "et al." (1999) and Gregan "et al." (2001a). The GMN motif location is indicated in red and the TM domains in light blue. The orientation in the membrane and the positions of the N- and C-termini are indicated. The various sizes of the soluble domains are given in amino acids (AA). TM domains are numbered. Not drawn to scale.

Mrs2p has been localised to the mitochondrial inner membrane by subcellular fractionation and immunodetection and Lpe10p to the mitochondria. Mitochondria lacking Mrs2p do not show a fast Mg²⁺ uptake, but only a slow ‘leak’, and overaccumulation of Mrs2p leads to an increase in the initial rate of uptake. Additionally CorA, when fused to the mitochondrial leader sequence of Mrs2p, can partially complement the mitochondrial defect conferred by the loss of either Mrs2p or Lpe10p. Hence, Mrs2p and/or Lpe10p may be the major Mg²⁺ uptake system for mitochondria. An intriguing possibility is that the proteins form heterodimers, as neither protein (when overexpressed) can fully complement the loss of the other.

The characteristics of Mg²⁺ uptake into isolated mitochondria by Mrs2p were quantified using mag-fura 2. The uptake of Mg²⁺ by Mrs2p shared a number of attributes with CorA. First, Mg²⁺ uptake was directly dependent on the electric potential (ΔΨ) across the boundary membrane. Second, the uptake is saturated far below that which the ΔΨ theoretically permits. Thus, the transport of Mg²⁺ by Mrs2p is likely to be regulated in a similar manner to CorA, possibly by the inactivation of the protein. Third, Mg²⁺ efflux was observed via Mrs2p upon the artificial depolarisation of the mitochondrial membrane by valinomycin. Finally, the Mg²⁺ fluxes through Mrs2p are inhibited by cobalt (III) hexaammine.

The kinetics of Mg²⁺ uptake by Mrs2p were determined as in the Froschauer "et al." (2004) paper on CorA in bacteria. The initial change in free Mg²⁺ concentration was 150 μM s-1 for wild type and 750 μM s-1 for mitochondria from yeast overexpressing MRS2. No attempt was made to scale the observed transport to the amount of transporter present.

Protozoan ("Paramecium")

The open reading frame for the XNTA gene is 1707 bp in size, contains two introns and produces a predicted protein of 550 amino acids. The protein has been predicted to contain 11 TM domains and also contains the α1 and α2 motifs (see figure) of the SLC8 (Na+/Ca²⁺ exchangercite journal| last=Quednau| first= B.D. | coauthors=Nicoll, D.A., and Philipson, K.D.|year=2004| title= The sodium/calcium exchanger family—SLC8| journal=Pflügers Archiv European Journal of Physiology| volume= 447| pages=543–548| doi= 10.1007/s00424-003-1065-4] ) and SLC24 (K+ dependent Na+/Ca²⁺ exchangercite journal| last=Schnetkamp| first= P.P.M.|year=2004| title= The SLC24 Na+/Ca²⁺-K⁺ exchanger family: vision and beyond| journal=Pflügers Archiv European Journal of Physiology| volume= 447| pages=683–688| doi=10.1007/s00424-003-1069-0] ) human solute transport proteins. The XntAp is equally similar to the SLC8 and SLC24 protein families by amino acid sequence, but the predicted TM topology is more like that of SLC24. In any case, the similarity is at best weak and the relationship is very distant. It is interesting to note that the AtMHX protein from plants also shares a distant relationship with the SLC8 proteins.

The figure shows the predicted TM topology of XntAp. Adapted from Haynes "et al." (2002), this figure shows the computer predicted membrane topology of XntAp in "Paramecium". The orientation in the membrane was determined using HMMTOPcite journal| last=Tusnady| first= G.E. | coauthors=Simon, I.|year=1998| title= Principles governing amino acid composition of integral membrane proteins: application to topology prediction| journal=Journal of Molecular Biology | volume=283| pages=489–506| doi= 10.1006/jmbi.1998.2107] cite journal| last=Tusnady| first= G.E. | coauthors=Simon, I.|year=2001| title= The HMMTOP transmembrane topology prediction server| journal=Bioinformatics | volume=17| pages=849–850| doi= 10.1093/bioinformatics/17.9.849| pmid=11590105] . The TM domains are shown in light blue. The α1 and α2 domains are shown in green. The orientation in the membrane and the positions of the N- and C-termini are indicated. Not drawn to scale.

The Mg²⁺-dependent currents carried by XntAp are kinetically like that of a channel protein, and have an ion selectivity order of Mg²⁺ > Co²⁺, Mn²⁺ > Ca²⁺ — a series again very similar to that of CorA. Unlike the other transport proteins reported so far, XntAp is dependent on intracellular Ca²⁺. The transport was also dependent on ΔΨ, but again Mg²⁺ is not transported to equilibrium, being limited to approximately 0.4 mM free Mg²⁺ in the cytoplasm. The existence of an intracellular compartment with a much higher free concentration of Mg²⁺ (8 mM) was also supported by the results.

Metazoa

The investigation of Mg²⁺ in animals, including humans, has lagged behind that in bacteria and yeast. This is largely because of the complexity of the systems involved, but it is also due to the impression within the field that Mg²⁺ was maintained at high levels within all cells and was unchanged by external influences. Only in the last 25 years has a series of reports begun to challenge this view, with new methodologies finding that free Mg²⁺ content is maintained at levels where changes might influence cellular metabolismcite journal| last=Romani| first= A.M.P. | coauthors=Maguire, M.E.|year=2002| title= Hormonal regulation of Mg²⁺ transport and homeostasis in eukaryotic cells| journal=BioMetals | volume=15| pages=271–283| doi=10.1023/A:1016082900838] .

MRS2

A bioinformatic search of the sequence databases identified one homologue of the MRS2 gene of yeast in a range of metazoans. The protein has a very similar sequence and predicted TM topology to the yeast protein, and the GMN motif is intact at the end of the first TM domain. The human protein, hsaMrs2p, has been localised to the mitochondrial membrane in mouse cells using a GFP fusion protein.

Very little is known with regard to the Mg²⁺ transport characteristics of the protein in mammals. However, Zsurka "et al." (2001) have shown that the human Mrs2p complements the mrs2 mutants in the yeast mitochondrial Mg²⁺ uptake system.

LC41 (MgtE)

The identification of this gene family in the metazoa began with a signal sequence trap method for isolating secreted and membrane proteins. Much of the identification has come from bioinformatic analyses. Three genes were eventually identified in humans, another three in mouse and three in "Caenorhabditis elegans", with a single gene in "Anopheles gambiae". The pFAM database lists the MgtE domain as pFAM01769 and additionally identifies an MgtE domain-containing protein in "Drosophila melanogaster". The proteins containing the MgtE domain can be divided into seven classes, as defined by pFAM using the type and organisation of the identifiable domains in each protein. Metazoan proteins are present in three of the seven groups. All of the metazoa proteins contain two MgtE domains. However, some of these have been predicted only by context recognition (Coin, Bateman and Durbin, unpublished. See the pFAM website for further details).

The human SLC41A1 protein contains two MgtE domains with 52% and 46% respective similarity to the PF01769 consensus sequence and is predicted to contain ten TM domains, five in each MgtE domain (see Figure). Incidentally, this structure suggests that the MgtE protein of bacteria may work as a dimer. Adapted from Wabakken "et al." (2003) and the pFAM database, the figure shows the computer predicted membrane topology of MgtE in "H. sapiens". The TM domains are shown in light blue. The orientation in the membrane and the positions of the N- and C-termini are indicated. The figure is not drawn to scale.

Wabakken "et al." (2003) found that the transcript of the SLC41A1 gene was expressed in all human tissues tested, but at varying levels. The tissues with the most abundant expression of the gene were the heart and testis. No explanation of the expression pattern has been suggested with regard to Mg²⁺-related physiology.

It has not been shown whether the SLC41 proteins transport Mg²⁺ or complement a Mg²⁺ transport mutation in any experimental system. However, it has been suggested that as MgtE proteins have no other known function, they are likely to be Mg²⁺ transporters in the metazoa as they are in the bacteria. This will need to be verified using one of the now standard experiment systems for examining Mg²⁺ transport.

TRPM6/ TRPM7

The TRPM family of ion channels has members throughout the metazoa. The TRPM6 and TRPM7 proteins are highly unusual, containing both an ion channel domain and a kinase domain (Figure 1.7). The role of the kinase domain brings about the most heated debate.

The activity of these two proteins has been very difficult to quantify. TRPM7 by itself appears to be a Ca²⁺ channelcite journal| last=Runnels| first= L.W. | coauthors=Yue, L., and Clapham, D.E.|year=2002| title= The TRPM7 channel is inactivated by PIP2 hydrolysis| journal=Nature Cell Biology| volume= 4| pages=329–336] but in the presence of TRPM6 the affinity series of transported cations places Mg²⁺ above Ca²⁺.cite journal| last=Monteilh-Zoller| first= M.K. | coauthors=Hermosura, M.C., Nadler, M.J.S., Scharenberg, A.M., Penner, R., and Fleig, A.|year=2003| title= TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions| journal=Journal of General Physiology| volume= 121| pages=49–60| doi= 10.1085/jgp.20028740| pmid=12508053] The differences in reported conductance were caused by the expression patterns of these genes. TRPM7 is expressed in all cell types tested so far, while TRPM6 shows a more restricted pattern of expressioncite journal| last=Chubanov| first= V. | coauthors=Waldegger, S., Mederos y Schnitzler, M., Vitzthum, H., Sassen, M.C., Seyberth, H.W., Konrad, M., and Gudermann, T.|year=2004| title= Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia| journal=PNAS | volume=101| pages=2894–2899| doi= 10.1073/pnas.0305252101| pmid=14976260] . An unfortunate choice of experimental system by Voets "et al.", (2004)cite journal| last=Voets| first= T. | coauthors=Nilius, B., Hoefs, S., van der Kemp, A.W.C.M., Droogmans, G., Bindels, R.J.M., and Hoenderop, J.G.J.|year=2004| title= TRPM6 forms the Mg²⁺ influx channel involved in intestinal and renal Mg²⁺ absorption| journal=Journal of Biological Chemistry | volume=279| pages=19–25| doi=10.1074/jbc.M311201200| pmid=14576148] led to the conclusion that TRPM6 is a functional Mg²⁺ transporter. However, later work by Chubanov "et al." (2004) clearly showed that TRPM7 is required for TRPM6 activity, and that the results of Voets "et al." are explained by the expression of TRPM7 in the experimental cell line used by Voets "et al." in their experiments. Whether TRPM6 is functional by itself is yet to be determined.

The predicted TM topology of the TPRM6 and TRPM7 proteinshave been adapted from Nadler "et al." (2001), Runnels "et al." (2001)cite journal| last=Runnels| first= L.W. | coauthors=Yue, L., and Clapham, D.E.|year=2001| title= TRP-PLIK, a bifunctional protein with kinase and ion channel activities| journal=Science| volume= 291| pages=1043–1047| doi= 10.1126/science.1058519| pmid=11161216] and Montell "et al." (2002), this figure shows the computer predicted membrane topology of the TRPM6 and TRPM7 proteins in "Homo sapiens". At this time the topology shown should be considered a tentative hypothesis. The TM domains are shown in light blue, the pore loop in purple, the TRP motif in red and the kinase domain in green. The orientation in the membrane and the positions of the N- and C-termini are indicated. Not drawn to scale.

The conclusions of the Voets "et al." (2004) paper are probably incorrect in attributing the Mg²⁺ dependent currents to TRPM7 alone, and their kinetic data are likely to reflect the combined TRPM7/ TRPM6 channel. The report presents a robust collection of data consistent with a channel-like activity passing Mg²⁺, based on both electrophysiological techniques and also mag-fura 2 to determine changes in cytoplasmic free Mg²⁺.

Claudin-16 (Paracellin-1, PCLN-1)

This gene is the only known example of Mg²⁺ transport via the paracellular pathway; that is, it mediates the transport of the ion through the tight junctions between cells that form an epithelial cell layer. In particular, Claudin-16 allows the selective reuptake of Mg²⁺ in the human kidney.

The gene Claudin-16 was cloned by Simon "et al." (1999), again only after a series of reports describing the Mg²⁺ flux itself with no gene/proteincite journal| last=Shareghi| first= G.R. | coauthors=Agus, Z.S.|year=1982| title= Magnesium transport in the cortical thick ascending limb of Henle's loop of the rabbit| journal=Journal of Clinical Investigation | volume=69| pages=759–769| doi= 10.1172/JCI110514] cite journal| last=di Stefano| first= A. | coauthors=Roinel, N., de Rouffignac, C., and Wittner, M.|year=1993| title= Transepithelial Ca²⁺ and Mg²⁺ transport in the cortical thick ascending limb of Henle's loop of the mouse is a voltage-dependent process| journal=Renal Physiology and Biochemistry| volume= 16| pages=157–166] cite journal| last=de Rouffignac| first= C. | coauthors=Quamme, G.|year=1994| title= Renal magnesium handling and its hormonal control| journal=Physiology Reviews| volume= 74| pages=305–322] . The expression pattern of the gene was determined by RT-PCR, and was shown to be very tightly confined to a continuous region of the kidney tubule running from the medullary thick descending limb to the distal convoluted tubule. This localisation was consistent with the earlier reports for the location of Mg²⁺ re-uptake by the kidney. Following the cloning, mutations in the gene were identified in patients with familial hypomagnesaemia with hypercalciuria and nephrocalcinosiscite journal| last=Weber| first= S. | coauthors=Hoffmann, K., Jeck, N., Saar, K., Boeswald, M., Kuwertz-Broeking, E., Meij, I.I.C., Knoers, N.V.A.M., Cochat, P., Sulakova, T., Bonzel, K.E., Soergel, M., Manz, F., Schaerer, K., Seyberth, H.W., Reis, A., and Konrad, M.|year=2000| title= Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene| journal=European Journal of Human Genetics| volume= 8| pages=414–422| doi= 10.1038/sj.ejhg.5200475] cite journal| last=Weber| first= S. | coauthors=Schneider, L., Peters, M., Misselwitz, J., Roennefarth, G., Boeswald, M., Bonzel, K.E., Seeman, T., Sulakova, T., Kuwertz-Broeking, E., Gregoric, A., Palcoux, J.-B., Tasic, V., Manz, F., Schaerer, K., Seyberth, H.W., and Konrad, M.|year=2001| title= Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis| journal=Journal of the American Society of Nephrology | volume=12| pages=1872–1881] , strengthening the links between the gene and the uptake of Mg²⁺.

Plants

The current knowledge of the molecular mechanisms for Mg²⁺ transport is plants is very limited, with only three publications reporting a molecular basis for Mg²⁺ transport in plants. However, the importance of Mg²⁺ to plants has been well described, and physiological and ecophysiological studies into the effects of Mg²⁺ are numerous. This section will summarise the knowledge of a gene family identified in plants that is distantly related to CorA. Another gene unrelated to this gene family and to CorA has also been identified. This Mg²⁺/H⁺ exchanger (AtMHX), localised to the vacuolar membrane, is described last.

The AtMRS2 gene family

Schock "et al." (2000) identified and named the family AtMRS2 based on the similarity of the genes to the MRS2 gene of yeast. The authors also showed that the AtMRS2-1 gene could complement a Δmrs2 yeast mutant phenotype. Independently, Li "et al." (2001) published a report identifying the family and showing that two additional members could complement Mg²⁺ transport deficient mutants, one in "S. typhimurium" and the other in "S. cerevisiae".

The three genes that have been shown to transport Mg²⁺ are AtMRS2-1, AtMRS2-10 and AtMRS2-11, and these genes produce proteins 442, 443 and 459 amino acids in size, respectively. Each of the proteins is predicted to have two TM domains, and each shows significant similarity to Mrs2p of yeast and a weak similarity to CorA of bacteria. All three proteins contain the conserved GMN amino acid motif at the outside end of the first TM domain.

The AtMRS2-1 gene, when expressed in yeast from the MRS2 promoter and being fused C-terminally to the first 95 amino acids of the Mrs2p protein, was directed to the mitochondria, where it complemented a Δmrs2 mutant both phenotypically (mitochondrial RNA splicing was restored) and with respect to the Mg²⁺ content of the organelle. No data on the kinetics of the transport were presented. The AtMRS2-11 gene was analysed in yeast (in the alr1alr2 strain), where it was shown that expression of the gene significantly increased the rate of Mg²⁺ uptake into starved cells over the control, as measured using flame atomic absorption spectroscopy of total cellular Mg²⁺ content. However, Alr1p was shown to be significantly more effective at transporting Mg²⁺ at low extracellular concentrations, suggesting that the affinity of AtMRS2-11 for Mg²⁺ is lower than that of Alr1p. An electrophysiological (voltage clamp) analysis of the AtMRS2-11 protein in Xenopus oocytes also showed a Mg²⁺-dependent current at membrane potentials (ΔΨ) of –100 – –150 mV insidecite journal| last=Tutone| first= A.F.|year=2004| title= Cloning and chararcterisation of the Mg²⁺ transport gene from A. thaliana. In School of Biological Sciences (Auckland: University of Auckland)] . These values are physiologically significant, as several membranes in plants maintain ΔΨ in this range. However, the author had difficulty reproducing these results due to an apparent ‘death’ of oocytes containing the AtMRS2-11 protein, and therefore these results should be viewed with caution.

The AtMRS2-10 transporter has been analysed using radioactive tracer uptake analysis. 63Ni²⁺ was used as the substitute ion and Mg²⁺ was shown to inhibit the uptake of 63Ni²⁺ with a Ki of 20 μM. Uptake was also inhibited by Co(III)Hex and by other divalent cations. Only Co²⁺ and Cu²⁺ inhibited transport with Ki values less than 1 mM.

The AtMRS2-10 protein was fused to GFP, and shown to be localised to the plasma membrane. A similar experiment was attempted in the Schock "et al." (2000) paper, but the observed localisation was not significantly different from that seen with unfused GFP. The most likely reason for the lack of a definitive localisation of AtMRS2-1 in the Schock "et al." paper is that the authors removed the TM domains from the protein, thereby precluding its insertion into a membrane.

The exact physiological significance of the AtMRS2-1 and AtMRS2-10 proteins in plants has yet to be clarified. The AtMRS2-11 gene has been overexpressed (from the CaMV 35S promoter) in A. thaliana. The transgenic line has been shown to accumulate high levels of the AtMRS2-11 transcript. A strong Mg²⁺ deficiency phenotype (necrotic spots on the leaves, see Chapter 1.5 below) was recorded during the screening process (in both the T1 and T2 generations) for a homozygote line. However, this phenotype was lost in the T3 generation and could not be reproduced when the earlier generations were screened a second time. The author suggested that environmental affects were the most likely cause of the inconsistent phenotype.

AtMHX

The first magnesium transporter isolated in any multicellular organism, AtMHX shows no similarity to any previously isolated Mg²⁺ transport protein. The gene was initially identified in the A. thaliana genomic DNA sequence database, by its similarity to the SLC8 family of Na+/Ca²⁺ exchanger genes in humans.

The cDNA sequence of 1990 bp is predicted to produce a 539-amino acid protein. AtMHX is quite closely related to the SLC8 family at the amino acid level and shares a topology with eleven predicted TM domains (Figure A10.5). There is one major difference in the sequence, however, in that the long non-membranal loop (see Figure A10.5) is 148 amino acids in the AtMHX protein but 500 amino acids in the SLC8 proteins. However, this loop is not well conserved and is not required for transport function in the SLC8 family.

The AtMHX gene is expressed throughout the plant but most strongly in the vascular tissue. The authors suggest that the physiological role of the protein is to store Mg²⁺ in these tissues for later release on need. The protein localisation to the vacuolar membrane supports this suggestion (see also Chapter 1.5).

The protein transports Mg²⁺ into the vacuolar space and H⁺ out, as demonstrated by electrophysiological techniques. The transport is driven by the ΔpH maintained between the vacuolar space (pH 4.5 – 5.9) and the cytoplasm (pH 7.3 – 7.6) by an H⁺-ATPasecite journal| last=Kurkdjian| first= A. | coauthors=Guern, J.|year=1989| title= Intracellular pH: measurement and importance in cell activity| journal=Annual Review of Plant Physiology and Plant Molecular Biology | volume=40| pages=271–303| doi= 10.1146/annurev.pp.40.060189.001415] cite book| last=Marschner| first= H.|year=1995| title= Mineral Nutrition in Higher Plants. (San Diego: Academic Press)] . How the transport of Mg²⁺ by the protein is regulated was not determined. Currents were observed to pass through the protein in both directions, but the Mg²⁺ out current required a ‘cytoplasmic’ pH of 5.5, a condition not found in plant cells under normal circumstances. In addition to the transport of Mg²⁺, Shaul "et al." (1999) also showed that the protein could transport Zn²⁺ and Fe²⁺, but did not report on the capacity of the protein to transport other divalent cations (e.g. Co²⁺ and Ni²⁺) or its susceptibility to inhibition by cobalt (III) hexaammine.

The detailed kinetics of Mg²⁺ transport have not been determined for AtMHX. However, physiological effects have been demonstrated. When A. thaliana plants were transformed with overexpression constructs of the AtMHX gene driven by the CaMV 35S promoter, the plants over-accumulated the protein. The plants showed a phenotype of necrotic lesions in the leaves, and the authors suggest that this is caused by a disruption in the normal function of the vacuole, given their observation that the total Mg²⁺ (or Zn²⁺) content of the plants was not altered in the transgenic plants.

The image has been adapted from Shaul "et al." (1999) and Quednau et al. (2004), and combined with an analysis using HMMTOP, this figure shows the computer predicted membrane topology of the AtMHX protein in "Arabidopsis thaliana". At this time the topology shown should be considered a tentative hypothesis. The TM domains are shown in light blue. The orientation in the membrane and the positions of the N- and C-termini are indicated. Not drawn to scale. The α1 and α2 domains (shown in green) are both quite hydrophobic and may both be inserted into the membrane.

References

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