Disease relevance of ATX1

• Hence, ATX1 protects cells against the toxicity of both superoxide anion and hydrogen peroxide [1].
• The unusual structure and dynamics of Atx1 suggest a copper exchange function for this protein and related domains in the Menkes and Wilson disease proteins [2].

High impact information on ATX1

• Atx1, a prototypical copper chaperone protein from yeast, has now been shown to act as a soluble cytoplasmic copper(I) receptor that can adopt either a two- or three-coordinate metal center in the active site [2].
• The ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity [1].
• This site is similar to those observed for the Atx1 family of copper chaperones and is consistent with reported mutagenesis studies [3].
• This equilibrium is unaffected by a 50-fold excess of the Cu(I) competitor, glutathione, indicating that Atx1 also protects Cu(I) from nonspecific reactions [4].
• A key physiological partner of the Saccharomyces cerevisiae Atx1 is Ccc2, a cation transporting P-type ATPase located in secretory vesicles [4].

Biological context of ATX1

• We demonstrate here that this vesicle protein normally functions in the homeostasis of manganese ions and that this role in metal metabolism is necessary for the ATX1 suppression of SOD1 deficiency [5].
• The iron deficiency of atx1 mutants is augmented by mutations in END3 blocking endocytosis, suggesting that a parallel pathway for intracellular copper trafficking is mediated by endocytosis [6].
• An ATX1 homologue of 503 bp length was cloned from a rat cDNA library, and the deduced protein from the cDNA was found to contain 68 amino acids with a predicted molecular mass of 7.2 kDa [7].
• In addition to Atx1p, we have recently uncovered an additional metal trafficking protein that appears to specifically deliver copper ions to SOD1 [8].
• RESULTS: The co-occurrence of gene families involved in Atx1p-mediated copper transport in the genomes and operon structures of 80 non-redundant prokaryotes was investigated [9].

Anatomical context of ATX1

• Atx1p localizes to the cytosol, and our studies indicate that it functions as a carrier for copper that delivers the metal from the cell surface Ctr1p to Ccc2p and then to Fet3p within the secretory pathway [6].

Associations of ATX1 with chemical compounds

• Copper-deprived S. cerevisiae cells expressing spao1(+) required a functional atx1(+) gene for growth on minimal medium containing ethylamine as the sole nitrogen source [10].
• In this study, cDNA and genomic clones encoding a homologue of the yeast gene anti-oxidant 1 (ATX1) from the white-rot fungus Trametes versicolor, a basidiomycete known to produce several laccase isoenzymes involved in lignin degradation, were identified [11].
• Copper trafficking to Ccc2p also relied on the lysine-rich face of Atx1p [12].
• Expression of wild type and mutant HAH1 in atx1 delta yeast revealed the essential role of these cysteine residues in copper trafficking to the secretory compartment in vivo, as expression of a Cys-12/Cys-15 double mutant abrogated copper incorporation into the multicopper oxidase Fet3p [13].
• The (1)H NMR solution structure of the Cu(I)-bound form of Atx1, a 73-amino acid metallochaperone protein from the yeast Saccharomyces cerevisiae, has been determined [14].

Other interactions of ATX1

• We now provide evidence that Atx1p helps deliver copper to the copper requiring oxidase Fet3p involved in iron uptake. atx1Delta null mutants are iron-deficient and are defective in the high affinity uptake of iron [6].
• Orthologues of the three copper chaperones characterized in yeast, ATX1, CCS and COX17, are present in Arabidopsis thaliana [15].
• A C-terminal domain of the membrane copper pump Ctr1 exchanges copper(I) with the copper chaperone Atx1 [16].

Analytical, diagnostic and therapeutic context of ATX1

• Molecular cloning of rat ATX1 homologue protein [7].
• Through site-directed mutagenesis, residues in the metal binding region including Lys65 were found to be necessary for both copper delivery to Ccc2p and for Atx1p antioxidant activity [12].

References