Magnesium transporter1 family

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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.

Contents

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]

Related Research Articles

Glycoprotein Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains (glycans) covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

Mannose Chemical compound

Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation are associated with mutations in enzymes involved in mannose metabolism.

Magnesium transporters are proteins that transport magnesium across the cell membrane. All forms of life require magnesium, yet the molecular mechanisms of Mg2+ uptake from the environment and the distribution of this vital element within the organism are only slowly being elucidated.

Acid alpha-glucosidase

Acid alpha-glucosidase, also called α-1,4-glucosidase and acid maltase, is an enzyme that helps to break down glycogen in the lysosome. It is functionally similar to glycogen debranching enzyme, but is on a different chromosome, processed differently by the cell and is located in the lysosome rather than the cytosol. In humans, it is encoded by the GAA gene. Errors in this gene cause glycogen storage disease type II.

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ADCY5

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GANC

Neutral alpha-glucosidase C is an enzyme that in humans is encoded by the GANC gene.

GANAB

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MAN1B1

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DAD1 Type of enzyme

Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunit DAD1 is an enzyme that in humans is encoded by the DAD1 gene.

An Error has occurred retrieving Wikidata item for infobox Magnesium transporter protein 1 is a protein that in humans is encoded by the MAGT1 gene.

NIPA1

Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 is a protein that in humans is encoded by the NIPA1 gene. This gene encodes a potential transmembrane protein which functions either as a receptor or transporter molecule, possibly as a magnesium transporter. This protein is thought to play a role in nervous system development and maintenance. Alternative splice variants have been described, but their biological nature has not been determined. Mutations in this gene have been associated with the human genetic disease autosomal dominant spastic paraplegia 6.

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SLC41A1

SLC41A1 is a protein that in humans is encoded by the gene SLC41A1. It is homologous to the prokaryotic Mg++ transfer protein MgtE

XMEN disease Medical condition

XMEN disease is a rare genetic disorder of the immune system that illustrates the role of Mg2+ in cell signaling. XMEN stands for “X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia.” The disease is characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Investigators in the laboratory of Dr. Michael Lenardo, National Institute of Allergy and Infectious Diseases at the National Institutes of Health first described this condition in 2011.

Stt3a, catalytic subunit of the oligosaccharyltransferase complex

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Metal transporter CNNM3 is a human transmembrane protein which is made up of 707 amino acids. Although CNNM3 is ubiquitous, it is mostly present in the kidney, brain, lung, spleen, heart and liver.

References

  1. 1 2 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. 1 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. 1 2 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. 1 2 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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