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1.A.76 The Magnesium Transporter1 (MagT1) Family 

Intracellular magnesium is abundant, highly regulated and plays an important role in biochemical functions. Unique mammalian Mg2+ transporters have been biochemically identified. Goytain and Quamme 2005 identified a Mg2+ transporter encoded by an implantation-associated protein precursor, IAP, that is regulated by magnesium. They designated this protein, MagT1. MagT1 is of 335 amino acids and possesses five TMSs with an N-terminal cleavage site and a number of phosphorylation sites. When expressed in Xenopus laevis oocytes, MagT1 mediates saturable Mg2+ uptake with a Michaelis constant of 0.23 mM. Transport of Mg2+ by MagT1 is rheogenic, voltage-dependent, and does not display time-dependent inactivation. Transport is specific to Mg2+ as other divalent cations do not evoke currents. Large external concentrations of some cations inhibited Mg2+ transport (Ni2+, Zn2+, Mn2+) in MagT1-expressing oocytes although Ca2+and Fe2+ were without effect (Goytain and Quamme 2005).  MagT1 has an N-terminal thioredoxin domain (Trx family) of unknown function.


MagT1 and its homologues are called tumor suppressor candidate 3 genes and oligosaccharidyl transferase. They are found in various eukaryotes (animals, plants, fungi etc.).
The identification of genetic changes and their functional consequences in patients with immunodeficiency revealed that magnesium and MAGT1 are key molecular players for T cell-mediated immune responses (Trapani et al. 2015). This led to the description of XMEN (X-linked immunodeficiency with magnesium defect, Epstein Barr Virus infection, and neoplasia) syndrome, for which Mg2+ supplementation has been shown to be beneficial. Similarly, the identification of a copy-number variation (CNV) leading to dysfunctional MAGT1 in a family with atypical ATRX syndrome and skin abnormalities, suggested that the MAGT1 defect is responsible for the cutaneous problems. Recent genetic investigations questioned the previously proposed role for MAGT1 in intellectual disability (Trapani et al. 2015). Expression levels of MAGT1 may be biomarkers for the diagnosis and prognosis of several types of cancer (Molee et al. 2015).
 

Zhou and Clapham 2009 identified two mammalian genes, MagT1 and TUSC3, catalyzing Mg2+ influx. MagT1 is universally expressed in all human tissues, and its expression level is up-regulated in low extracellular Mg2+. Knockdown of either MagT1 or TUSC3 protein lowered the total and free intracellular Mg2+ concentrations in mammalian cell lines. Morpholino knockdown of MagT1 and TUSC3 protein expression in zebrafish embryos resulted in early developmental arrest; excess Mg2+ or supplementation with mammalian mRNAs rescued these effects. Thus, MagT1 and TUSC3 are vertebrate plasma membrane Mg2+ transport system (Zhou and Clapham 2009).

The reaction catalyzed by MagT1 is:

Mg2+ (out) → Mg 2+ (in)

References associated with 1.A.76 family:

Goytain, A. and G.A. Quamme. (2005). Identification and characterization of a novel mammalian Mg2+ transporter with channel-like properties. BMC Genomics 6: 48. 15804357
Molee, P., P. Adisakwattana, O. Reamtong, S. Petmitr, T. Sricharunrat, N. Suwandittakul, and U. Chaisri. (2015). Up-regulation of AKAP13 and MAGT1 on cytoplasmic membrane in progressive hepatocellular carcinoma: a novel target for prognosis. Int J Clin Exp Pathol 8: 9796-9811. 26617690
Trapani, V., N. Shomer, and E. Rajcan-Separovic. (2015). The role of MAGT1 in genetic syndromes. Magnes Res 28: 46-55. 26422833
Zhou, H. and D.E. Clapham. (2009). Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc. Natl. Acad. Sci. USA 106: 15750-15755. 19717468