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9.B.20 The Putative Mg2+ Transporter-C (MgtC) Family 

The MgtC protein of Salmonella typhimurium is encoded by a gene found upstream of the mgtB gene and probably within the same operon (mgtCBR) with it. The MgtB protein is known to be a Mg2+-transporting P-type ATPase (TC #3.A.3). It was suggested on the basis of gene proximity without direct experimental evidence that MgtC is an auxiliary protein for MgtB function. However, in Mycobacterium tuberculosis, a close MgtC homologue is found in a region of the genome that does not encode a comparable MgtB homologue. Moreover, loss of MgtC, due to an mgtC knock-out mutation, prevents growth of the bacteria at low Mg2+ concentrations (10-50 µM) under low pH conditions (pH 6.2 - 6.8). Growth was restored at higher concentrations of Mg2+ (100 µM) (Alix and Blanc-Potard, 2007). The results are consistent with a Mg2+ uniport or a Mg2+:H+ antiport mechanism, but a transport function for MgtC has not been established. MgtC (but not MgtB) is essential for virulence. Synthesis is regulated by MgtR and an antisense RNA termed AmgR (Lee and Groisman, 2010).  Roles of MgtC homologues in intramacrophage bacterial survival have been discussed (Alix and Blanc-Potard 2007).

The MgtC proteins of S. typhimurium and M. tuberculosis and the SapB protein of Bacillus subtilis exhibit 4-6 putative TMSs. Homologues are found in several bacteria including cyanobacteria, but not in archaea or eukaryotes. Most of these proteins are of a similar size, but a few are reported to be substantially smaller than the three proteins cited above. For example, SrpB of Synechococcus PCC7942, a cyanobacterial plasmid-encoded protein, which is transcriptionally induced by sulfur deprivation and controlled by the CysR protein, is 182 residues long. Some archaeal and bacterial homologues are large (400-600aas) and have 14 TMS in a 5+5+7 arrangement (see family proteins 9.B.20.3.1-3).

Günzel et al. (2006) have provided some characteristics of MgtC from Salmonella enterica. This protein is required for virulence in mice. They could not obtain evidence for a transport function, but noted that in eukaryotic cells, it activates the Na+, K+-ATPase. Moreover, Alix and Blanc-Potard (2007) summarized evidence that MgtC is required for the intramacrophage survival of several pathogens. They believe that this function may be unrelated to the ability of MgtC to promote survival at low Mg2+.

MgtC is required for intramacrophage replication of intracellular pathogens and growth in low Mg2+ medium. A link between these two phenotypes has been proposed due to putative Mg2+ deprivation inside the phagosome. MgtC is part of a family of proteins that share a conserved N-terminal transmembrane domain and a variable C-terminal domain. The Salmonella MgtC C-terminal domain is cytoplasmic, adopts a fold also found in metal transporters and RNA interacting domain, and does not bind Mg2+. MgtC homologues from diverse gamma-proteobacteria have been expressed in a Salmonella ΔmgtC strain. The Y. pestis MgtC fully replaced the Salmonella MgtC whereas P. luminescens or P. aeruginosa MgtC complemented only in low Mg2+ medium, thus dissociating the two MgtC-related phenotypes.

MgtC is a dimer, bearing an ACT-like domain (Yang et al. 2012). A mutant lacking the mgtC gene exhibited increased cellulose levels due to increased expression of the cellulose synthase gene bcsA and of cyclic diguanylate, the allosteric activator of the BcsA protein (Pontes et al. 2015).

References associated with 9.B.20 family:

Alix, E. and A.B. Blanc-Potard. (2007). MgtC: a key player in intramacrophage survival. Trends Microbiol. 15: 252-256. 17416526
Bernut, A., C. Belon, C. Soscia, S. Bleves, and A.B. Blanc-Potard. (2015). Intracellular phase for an extracellular bacterial pathogen: MgtC shows the way. Microb Cell 2: 353-355. 28357311
Gastebois, A., A.B. Blanc Potard, S. Gribaldo, R. Beau, J.P. Latgé, and I. Mouyna. (2011). Phylogenetic and functional analysis of Aspergillus fumigatus MGTC, a fungal protein homologous to a bacterial virulence factor. Appl. Environ. Microbiol. 77: 4700-4703. 21602378
Günzel, D., L.M. Kucharski, D.G. Kehres, M.F. Romero, and M.E. Maguire. (2006). The MgtC virulence factor of Salmonella enterica serovar Typhimurium activates Na(+),K(+)-ATPase. J. Bacteriol. 188: 5586-5594. 16855249
Ishijima, S., M. Uda, T. Hirata, M. Shibata, N. Kitagawa, and I. Sagami. (2015). Magnesium uptake of Arabidopsis transporters, AtMRS2-10 and AtMRS2-11, expressed in Escherichia coli mutants: Complementation and growth inhibition by aluminum. Biochim. Biophys. Acta. 1848: 1376-1382. 25772503
Lee, E.J. and E.A. Groisman. (2010). An antisense RNA that governs the expression kinetics of a multifunctional virulence gene. Mol. Microbiol. 76: 1020-1033. 20398218
Lee, J.W. and E.J. Lee. (2015). Regulation and function of the Salmonella MgtC virulence protein. J Microbiol 53: 667-672. 26231375
Mates, A.K., A.K. Sayed, and J.W. Foster. (2007). Products of the Escherichia coli acid fitness island attenuate metabolite stress at extremely low pH and mediate a cell density-dependent acid resistance. J. Bacteriol. 189: 2759-2768. 17259322
Moncrief, M.B.C. and M.E. Maguire (1998). Magnesium and the role of mgtC in growth of Salmonella typhimurium. Infect. Immun. 66: 3802-3809. 9673265
Nicholson, M.L. and D.E. Laudenbach (1995). Genes encoded on a cyanobacterial plasmid are transcriptionally regulated by sulfur availability and CysR. J. Bacteriol. 177: 2143-2150. 7536734
Park, M., D. Nam, D.H. Kweon, and D. Shin. (2018). ATP reduction by MgtC and Mg homeostasis by MgtA and MgtB enables Salmonella to accumulate RpoS upon low cytoplasmic Mg stress. Mol. Microbiol. 110: 283-295. 30112818
Pontes, M.H., E.J. Lee, J. Choi, and E.A. Groisman. (2015). Salmonella promotes virulence by repressing cellulose production. Proc. Natl. Acad. Sci. USA 112: 5183-5188. 25848006
Retamal, P., M. Castillo-Ruiz, and G.C. Mora. (2009). Characterization of MgtC, a virulence factor of Salmonella enterica Serovar Typhi. PLoS One 4: e5551. 19436747
Snavely, M.D., C.G. Miller, and M.E. Maguire. (1991). The mgtB Mg2+ transport locus of Salmonella typhimurium encodes a P-type ATPase. J. Biol. Chem. 266: 815-823. 1824701
Yang, Y., G. Labesse, S. Carrère-Kremer, K. Esteves, L. Kremer, M. Cohen-Gonsaud, and A.B. Blanc-Potard. (2012). The C-terminal domain of the virulence factor MgtC is a divergent ACT domain. J. Bacteriol. 194: 6255-6263. 22984256