Alternative titles; symbols
HGNC Approved Gene Symbol: ATOX1
Cytogenetic location: 5q33.1 Genomic coordinates (GRCh38): 5:151,742,822-151,758,631 (from NCBI)
Copper is one of the most prevalent transition metals in living organisms. Because free copper is toxic, copper homeostasis is tightly controlled by molecular mechanisms in which the metal is sequestered by protein carriers. ATOX1 is a copper chaperone that delivers copper to the metal-binding domains of the ATPase proteins ATP7A (300011) and ATP7B (606882). In an ATP-dependent process, ATP7A or ATP7B (depending on the cell type) translocates copper from the cytoplasm into the Golgi lumen for insertion into enzymes in the secretory pathway (summary by Hussain et al. (2008)).
Cells have highly specialized and complex systems for maintaining copper homeostasis which have been conserved through evolution. Yeast Atx1 encodes a cytosolic copper-binding protein that is essential for efficient high-affinity iron uptake and antioxidant defense. By screening a liver cDNA library, Klomp et al. (1997) isolated a full-length cDNA encoding ATOX1, the human homolog of Atx1, which they called HAH1 for 'human atx homolog-1.' The deduced 68-amino acid ATOX1 protein shares 47% identity with yeast Atx1, including conservation of the copper-binding domain and the lysine-rich C terminus. Northern blot analysis showed that ATOX1 was abundantly and ubiquitously expressed as a 0.5-kb transcript. Southern blot analysis showed that the ATOX1 gene exists as a single copy in the haploid genome.
Moore et al. (2002) investigated the tissue-specific localization of mouse Atox1. Immunohistochemical studies in liver localized the copper chaperone to hepatocytes surrounding both hepatic and central veins. In kidney, Atox1 localized to the cortex and the medulla. Cortex immunostaining was specific to glomeruli in both the juxtamedullary and cortical nephrons. Expression in the medulla appeared to be associated with the loops of Henle. These data suggested that localized regions in the liver and kidney express ATOX1 and have a role in copper homeostasis and/or antioxidant protection.
Klomp et al. (1997) showed that human ATOX1 complemented Atx1-null yeast strains. By analogy to yeast, they suggested that ATOX1 binds and delivers cytosolic copper to ATP7A and ATP7B in the trans-Golgi network. In addition to a role for ATOX1 in copper homeostasis, Klomp et al. (1997) proposed that, analogous to yeast, copper proteins dependent upon ATOX1 are important in cellular antioxidant defense.
By mutation analysis, Hussain et al. (2008) found that the highly conserved residues met10 and lys60 in human ATOX1 were critical for copper retention. Mutation of either of these residues to alanine increased the rate and extent of copper transfer from ATOX1 to a copper chelator.
Klomp et al. (1997) mapped the ATOX1 gene to chromosome 5q32-q33 by fluorescence in situ hybridization.
Boultwood et al. (2000) mapped the ATOX1 gene to the 3-Mb critical region of gene loss of the 5q- syndrome (153550) within 5q32, flanked by the genes for ADRB2 (109690) and IL12B (161561), using gene dosage analysis. Fine physical mapping studies by screening YAC and BAC contigs spanning the critical region of the 5q- syndrome showed that ATOX1 maps immediately adjacent to the SPARC gene (182120). Boultwood et al. (2000) suggested that ATOX1 represents a candidate gene for the 5q- syndrome.
Crystal Structure
Alvarez et al. (2010) described how tetrathiomolybdate (TM) inhibits proteins that regulate copper physiology. Crystallographic results revealed that the surprising stability of the drug complex with the metallochaperone Atx1 arises from formation of a sulfur-bridged copper-molybdenum cluster reminiscent of those found in molybdenum and iron sulfur proteins. Spectroscopic studies indicated that this cluster is stable in solution and corresponds to physiologic clusters isolated from TM-treated Wilson disease (277900) animal models. Finally, mechanistic studies showed that the drug-metallochaperone inhibits metal transfer functions between copper-trafficking proteins. Alvarez et al. (2010) concluded that their results are consistent with a model wherein TM can directly and reversibly downregulate copper delivery to secreted metalloenzymes.
Hamza et al. (2001) found that Atox1-null mice failed to thrive immediately after birth, with 45% of pups dying before weaning. Surviving animals exhibited growth failure, skin laxity, hypopigmentation, and seizures because of perinatal copper deficiency. Maternal Atox1 deficiency markedly increased the severity of the phenotype in the null progeny, resulting in increased perinatal mortality as well as severe growth retardation and congenital malformations among surviving Atox1 -/- progeny. Furthermore, Atox1-deficient cells accumulated high levels of intracellular copper, and metabolic studies indicated that this defect was caused by impaired cellular copper efflux. Taken together, these data revealed a direct role for Atox1 in trafficking of intracellular copper to the secretory pathway of mammalian cells and demonstrated that this metallochaperone plays a critical role in perinatal copper homeostasis.
Alvarez, H. M., Xue, Y., Robinson, C. D., Canalizo-Hernandez, M. A., Marvin, R. G., Kelly, R. A., Mondragon, A., Penner-Hahn, J. E., O'Halloran, T. V. Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. Science 327: 331-334, 2010. [PubMed: 19965379] [Full Text: https://doi.org/10.1126/science.1179907]
Boultwood, J., Strickson, A. J., Jabs, E. W., Cheng, J.-F., Fidler, C., Wainscoat, J. S. Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene. Hum. Genet. 106: 127-129, 2000. [PubMed: 10982193] [Full Text: https://doi.org/10.1007/s004399900215]
Hamza, I., Faisst, A., Prohaska, J., Chen, J., Gruss, P., Gitlin, J. D. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc. Nat. Acad. Sci. 98: 6848-6852, 2001. [PubMed: 11391006] [Full Text: https://doi.org/10.1073/pnas.111058498]
Hussain, F., Olson, J. S., Wittung-Stafshede, P. Conserved residues modulate copper release in human copper chaperone Atox1. Proc. Nat. Acad. Sci. 105: 11158-11163, 2008. [PubMed: 18685091] [Full Text: https://doi.org/10.1073/pnas.0802928105]
Klomp, L. W. J., Lin, S.-J., Yuan, D. S., Klausner, R. D., Culotta, V. C., Gitlin, J. D. Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J. Biol. Chem. 272: 9221-9226, 1997. [PubMed: 9083055] [Full Text: https://doi.org/10.1074/jbc.272.14.9221]
Moore, S. D. P., Helmle, K. E., Prat, L. M., Cox, D. W. Tissue localization of the copper chaperone ATOX1 and its potential role in disease. Mammalian Genome 13: 563-568, 2002. [PubMed: 12420134] [Full Text: https://doi.org/10.1007/s00335-002-2172-9]