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:
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.
Goytain, A. and G.A. Quamme. (2005). Identification and characterization of a novel mammalian Mg²⁺ transporter with channel-like properties. BMC Genomics 6: 48.
Gyimesi, G. and M.A. Hediger. (2022). Systematic in silico discovery of novel solute carrier-like proteins from proteomes. PLoS One 17: e0271062.
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.
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]
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.
Trapani, V., N. Shomer, and E. Rajcan-Separovic. (2015). The role of MAGT1 in genetic syndromes. Magnes Res 28: 46-55.
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.
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]
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.
Examples:
TC#	Name	Organismal Type	Example
1.A.76.1.1	Magnesium transporter, MagT1; Ost3_Ost6; SLC58A1 (Goytain and Quamme, 2005; Schmitz et al., 2007; Zhou and Clapham, 2009; Gyimesi and Hediger 2022). As of 2018, the function of this protein as a Mg²⁺ transporter was under debate (Schäffers et al. 2018). This protein is of 335 aas with 5 TMSs in a 1 (N-terminal) + 2 + 2 (C-terninal) TMS arrangement.	Eukaryotes	*MagT1 of Homo sapiens* (Q9H0U3)**

1.A.76.1.10	Ost3/Ost6 homologue of 334 aas and 5 TMSs		Ost3-like protein of Chlamydomonas reinhardtii (Chlamydomonas smithii)

1.A.76.1.11	Uncharacterized protein of 277 aas		UP of Reticulomyxa filosa

1.A.76.1.12	Uncharacterized protein of 362 aas		*UP of Naegleria gruberi* (Amoeba)**

1.A.76.1.13	Uncharacterized protein of 328 aas and 7 (or 5) TMSs		UP of Tetrapisispora blattae (Yeast) (Kluyveromyces blattae)

1.A.76.1.14	Mg²⁺ transporter, MagT1 homologue of 331 aas		MagT1 homologue of Pyronema omphalodes

1.A.76.1.2	Mg²⁺ transporter; also called Tumor suppressor candidate 3 isoform a, Tusc3a (69% identity with MagT1) (Zhou and Clapham, 2009). It can transport Mg²⁺, Fe²⁺, Cu²⁺ and Mn^Fe (Gyimesi and Hediger 2022).	Animals	*Tusc3a of Homo sapiens* (Q13454)**

1.A.76.1.3	Magnesium transporter protein 1 (MagT1) with a thioredoxin domain (residues 50 - 150) and an Ost3/Ost6 domain (residues 160 - 310 with 4 TMSs).	Animals	MagT1 of Danio rerio

1.A.76.1.4	Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 3	Amoeba	Ost3 of Dictyostelium discoideum

1.A.76.1.5	Ubiquitin conjugating enzyme of 345 aas with 4 C-terminal TMSs	Alveolata	Ubiquitin conjugating enzyme of Oxytricha trifallax

1.A.76.1.7	Putative magnesium transport protein of 354 aas and 4 C-terminal TMSs.		MagT1 homologue of Albugo laibachii

1.A.76.1.8	Glycosyl transferase, Ost3 of 350 aas and 4 TMSs. This protein is a subunit of the yeast oligosaccharyltransferase complex involved in N-glycosylation (Wild et al. 2018). It is not the catalytic subunit (see TC# 9.B.142.3.14).		Ost3 of Saccharomyces cerevisiae

1.A.76.1.9	Ost6-like protein of 332 aas and 4 TMSs.		*Ost6 of Saccharomyces cerevisiae* (Baker's yeast)**

Examples:
TC#	Name	Organismal Type	Example
1.A.76.2.1	Oligosaccharyltransferase complex/magnesium transporter family protein of 173 aas and 3 or 4 TMSs. The proteins in this family are part of a complex of eight ER proteins that transfers core oligosaccharide from dolichol carrier to Asn-X-Ser/Thr motifs. This family includes both OST3 and OST6, each of which contains four predicted transmembrane helices. Disruption of OST3 and OST6 leads to a defect in the assembly of the complex. Hence, the function of these genes seems to be essential for recruiting a fully active complex necessary for efficient N-glycosylation.	Plants	*Uncharacterized protein of Arabidopsis thaliana* (Mouse-ear cress)**

1.A.76.2.10	OstCL of 119 aas and 3 TMSs in a 1 + 2 TMS arrangement.		OstCL of Homo sapiens

1.A.76.2.2	Uncharacterized protein of 148 aas and 3 TMSs	Diplomonadida	UP of Giardia intestinalis (Giardia lamblia)

1.A.76.2.3	Uncharacterized protein of 159 aas and 3 TMSs	Rhodophyta	UP of Cyanidioschyzon merolae

1.A.76.2.4	Uncharacterized protein of 433 aas with 3 N-terminal TMSs.		*UP of Dictyostelium discoideum* (Slime mold)**

1.A.76.2.5	Oligosaccharyl transferase complex subunit, EgrG of 144 aas and 3 TMSs.		*OST3 family member of Echinococcus granulosus* (Hydatid tapeworm)**

1.A.76.2.6	OST3/OST6 superfamily protein of 158 aas and 3 TMSs.		OST3 family protein of 158 aas

1.A.76.2.7	OST3/OST6 Family protein of 159 aas and 3 TMSs.		OST3 homologue of Trichomonas vaginalis

1.A.76.2.8	Oligosaccharidyl transferase DS2 of 173 aas and 4 TMSs		DS2 of Loa loa (Eye worm) (Filaria loa)

1.A.76.2.9	Oligosaccharidyl transferase, OstC of 149 aas and 3 TMSs in a 1 + 2 TMS arrangement. It may be involved in sperm membrane integrity (Illa et al. 2021). OSTA and OSTC are useful self-assessment tools for osteoporosis detection (Bui et al. 2022).		OstC of Homo sapiens