A yeast metal resistance protein similar to human cystic fibrosis transmembrane conductance regulator (CFTR) and multidrug resistance-associated protein.

Abstract

Members of the ATP binding cassette (ABC) protein superfamily transport a variety of substances across biological membranes, including drugs, ions, and peptides.The yeast cadmium factor (YCFl ) gene from Saccharomyces cerevisiae is required for cadmium resistance and encodes a 1,515 amino acid protein with extensive homology to both the human multidrug resistance-associated protein (MRP1) and the cystic fibrosis transmembrane conductance regulator (hCFTR).S. cerevisiae cells harboring a deletion of the YCFl gene are hypersensitive to cadmium compared with wild type cells.Mutagenesis experiments demonstrate that conserved amino acid residues, functionally critical in hCFTR, play a vital role in YCF1-mediated cadmium resistance.Mutagenesis of phenylalanine 713 in the YCFl nucleotide binding fold 1, which correlates with the AF508 mutation found in the most common form of cystic fibrosis, completely abolished YCFl function in cadmium detoxification.Furthermore, substitution of a serine to alanine residue in a potential protein kinase A phosphorylation site in a central region of YCF1, which displays sequence similarity to the central regulatory domain of hCFTR, also rendered YCFl nonfunctional.These results suggest that YCFl is composed of modular domains found in human proteins which function in drug and ion transport.Metals serve both essential and toxic roles in biological systems.For example, copper is an essential metal which serves as a co-factor for a wide variety of enzymatic reactions; however, this same metal is highly toxic when present at elevated environmental concentrations.The metal cadmium, however, is of no known biological utility but is highly toxic a t relatively low concentrations.This difference in the biological utility of copper and cadmium may be due to their chemically distinct nature with respect to their ability to engage in oxidation-reduction reactions, ionic radii, coordination chemistry, and other properties (1).Cadmium pollution is a particularly important problem in metal toxicity due to the deposition of this toxic and