Magnesium transporter1 family

The Magnesium Transporter 1 (MagT1) Family (TC# 1.A.76) is a group of magnesium transporters that are part of the TOG superfamily. Goytain and Quamme identified a Mg2+--related transporter whose expression or function was affected by an implantation-associated protein precursor.[1] They designated this protein, MagT1. MagT1 is expressed as a 335 amino acid polypeptide which includes five transmembrane helices. The nascent polypeptide possesses a cleavage site after the N-terminal signal sequence helix, rendering a mature MagT1 protein with four transmembrane helices. MagT1 additionally contains a number of phosphorylation sites.

Recent evidence demonstrates that the primary function of MagT1 is protein glycosylation, mediated by MagT1's function as a component of the oligosaccharyltransferase (OST).[2][3]

Function

When expressed in Xenopus laevis oocytes, MagT1 mediates saturable Mg2+ uptake with a Km 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.[1] MagT1 has an N-terminal thioredoxin domain of unknown function.

Zhou and Clapham identified two mammalian genes, MagT1 and TUSC3, catalyzing Mg2+ influx.[4] MagT1 is universally expressed in all human tissues, and its expression level is upregulated 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.[4]

Transport reaction

The reaction catalyzed by MagT1, or a potential downstream glycosylation target (e.g. a Mg2+ transporter), is:

Mg2+ (out) → Mg2+ (in)

Role in magnesium deficiency

The identification of genetic changes and their functional consequences in patients with immunodeficiency resulting from loss of MAGT1 revealed that magnesium and MagT1 are key molecular players for T cell-mediated immune responses.[5] This led to the description of XMEN (X-linked immunodeficiency with magnesium defect, Epstein-Barr Virus infection, and neoplasia) syndrome,[6] for which Mg2+ supplementation has been shown to be beneficial.[7] Similarly, the identification of copy-number variation leading to dysfunctional MAGT1 in a family with atypical ATR-X syndrome and skin abnormalities, suggested that the MAGT1 defect is responsible for the cutaneous problems.

Role in protein glycosylation

MagT1 and its homologue TUSC3 are both bona fide components of the oligosaccharyltransferase (OST).[2][3]

References
  1. Goytain A, Quamme GA (April 2005). "Identification and characterization of a novel mammalian Mg2+ transporter with channel-like properties". BMC Genomics. 6: 48. doi:10.1186/1471-2164-6-48. PMC 1129089. PMID 15804357.
  2. Matsuda-Lennikov M, Biancalana M, Zou J, Ravell JC, Zheng L, Kanellopoulou C, et al. (September 2019). "N-linked glycosylation and expression of immune-response genes". The Journal of Biological Chemistry. 294 (37): 13638–13656. doi:10.1074/jbc.RA119.008903. PMC 6746436. PMID 31337704.
  3. Ravell JC, Matsuda-Lennikov M, Chauvin SD, Zou J, Biancalana M, Deeb SJ, et al. (January 2020). "Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease". The Journal of Clinical Investigation. 130 (1): 507–522. doi:10.1172/JCI131116. PMC 6934229. PMID 31714901.
  4. Zhou H, Clapham DE (September 2009). "Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development". Proceedings of the National Academy of Sciences of the United States of America. 106 (37): 15750–5. Bibcode:2009PNAS..10615750Z. doi:10.1073/pnas.0908332106. PMC 2732712. PMID 19717468.
  5. Trapani V, Shomer N, Rajcan-Separovic E (June 2015). "The role of MAGT1 in genetic syndromes". Magnesium Research. 28 (2): 46–55. doi:10.1684/mrh.2015.0381. PMID 26422833.
  6. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, et al. (July 2011). "Second messenger role for Mg2+ revealed by human T-cell immunodeficiency". Nature. 475 (7357): 471–6. doi:10.1038/nature10246. PMC 3159560. PMID 21796205.
  7. Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P, Zheng L, et al. (July 2013). "Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D". Science. 341 (6142): 186–91. Bibcode:2013Sci...341..186C. doi:10.1126/science.1240094. PMC 3894782. PMID 23846901.

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