Intracellular Pathways of Copper Trafficking in Yeast and Humans

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Abstract
In the bakers yeast S. cerevisiae, there at least four intracellular targets requiring copper ions- 1) Ccc2p and Fet3p in the secretory pathway (homologues to Menkes/Wilson proteins and ceruloplasmin); 2) cytochrome oxidase in the mitochondria; 3) copper transcription factors in the nucleus; and 4) Cu/Zn Superoxide dismutase (SOD1) in the cytosol. We have discovered a small soluble copper carrier that specifically delivers copper ions to the secretory pathway. This 8.2 kDa factor known as Atxlp, exhibits striking homology to the MERp mercury carrier of bacteria and contains a single MTCXXC metal binding site also found in the Menkes/Wilson family of copper transporting ATPases. Our studies show that Atxlp is cytosolic and facilitates the delivery of copper ions from the cell surface copper transporter to Ccc2p and Fet3p in the secretory pathway; furthermore, it is not involved in the delivery of copper ions to the mitochondria, the nucleus or cytosolic SOD1, implicating specific signals directing Atx 1p to the secretory pathway. Homologues to Atx 1p have been found in invertebrates, plants and humans, and the human gene is abundantly expressed in all tissues. In addition to Atx 1p, we have recently uncovered an additional metal trafficking protein that appears to specifically deliver copper ions to SOD1. Mutants in the corresponding gene (lys 7) are defective for SOD1 activity, and are unable to incorporate copper into SOD1, while there is no obvious impairment in copper delivery to cytochrome oxidase or Fet3p. The encoded 27 kDa protein contains a single MHCXXC consensus copper binding sequence and close homologues have been identified in a wide array of eukaryotic species including humans.