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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 long and possesses five TMSs with an N-terminal cleavage site and a number of phosphorylation sites. Most MagT1 proteins have 3 or 4 TMSs, where the first TMS in the 4 TMS proteins is of low hydrophobicity, and can be seen in must members of the family.  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 systems (Zhou and Clapham 2009). Magnetic fields boost Mg2+ transport efficiency via MagT1 from PLLA bone scaffold (Yan et al. 2023), and transient water wires mediate selective proton transport in designed channel proteins such as MagT1 (Kratochvil et al. 2023).

The reaction catalyzed by MagT1 is:

Mg2+ (out) → Mg 2+ (in)

References associated with 1.A.76 family:

Bui, M.H., P.T. Dao, Q.L. Khuong, P.A. Le, T.T. Nguyen, G.D. Hoang, T.H. Le, H.T. Pham, H.T. Hoang, Q.C. Le, and X.T. Dao. (2022). Evaluation of community-based screening tools for the early screening of osteoporosis in postmenopausal Vietnamese women. PLoS One 17: e0266452. 35381025
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
Gyimesi, G. and M.A. Hediger. (2022). Systematic in silico discovery of novel solute carrier-like proteins from proteomes. PLoS One 17: e0271062. 35901096
Illa, S.K., S. Mukherjee, S. Nath, and A. Mukherjee. (2021). Genome-Wide Scanning for Signatures of Selection Revealed the Putative Genomic Regions and Candidate Genes Controlling Milk Composition and Coat Color Traits in Sahiwal Cattle. Front Genet 12: 699422. 34306039
Kratochvil, H.T., L.C. Watkins, M. Mravic, J.L. Thomaston, J.M. Nicoludis, N.H. Somberg, L. Liu, M. Hong, G.A. Voth, and W.F. DeGrado. (2023). Transient water wires mediate selective proton transport in designed channel proteins. Nat Chem. [Epub: Ahead of Print] 37308712
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
Wild, R., J. Kowal, J. Eyring, E.M. Ngwa, M. Aebi, and K.P. Locher. (2018). Structure of the yeast oligosaccharyltransferase complex gives insight into eukaryotic N-glycosylation. Science 359: 545-550. 29301962
Yan, Z., T. Sun, W. Tan, Z. Wang, J. Yan, J. Miao, X. Wu, P. Feng, and Y. Deng. (2023). Magnetic Field Boosts the Transmembrane Transport Efficiency of Magnesium Ions from PLLA Bone Scaffold. Small e2301426. [Epub: Ahead of Print] 37271895
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