In vivo specificity of Ure2 protection from heavy metal ion and oxidative cellular damage in Saccharomyces cerevisiae.
The S. cerevisiae Ure2 protein is a prion precursor able to form large homopolymers with the characteristics of amyloid particles, a function largely restricted to its 90 N-terminal amino acids. The remaining C-terminal domain of Ure2 plays two important roles in cellular metabolism. First, it regulates nitrogen catabolic gene expression by forming a complex with the GATA transcription factor Gln3. This complex formation correlates with Gln3 being sequestered in the cytoplasm under conditions of excess nitrogen, where Gln3/Gat1-mediated transcription is minimal. Second, Ure2, which possesses structural homology with glutathione S-transferases and binds to xenobiotics and glutathione, has been recently shown to be required for Cd(II) and hydrogen peroxide detoxification. Present experiments demonstrate that Ure2 possesses a far broader protection specificity, being required to avoid the toxic effects of As(III), As(V), Cr(III), Cr(VI), Se(IV), as well as Cd(II) and Ni(II), and to varying lesser degrees Co(II), Cu(II), Fe(II), Ag(I), Hg(II), cumene and t-butyl hydroperoxides. In contrast, deletion of URE2 greatly enhances a cell's ability to withstand toxic concentrations of Zn(II) and Mo(VI). In the case of Cd(II), Ure2 does not function to decrease intracellular Cd(II) levels or influence glutathione availability for glutathionation. In fact, ure2 hypersensitivity to Cd(II) remains the same, even when glutathione is used as sole source of nitrogen for cell growth. These data suggest that Ure2 possesses a central role in metal ion detoxification, a role not demonstrably shared by either of the two known S. cerevisiae glutathione S-transferases, Gtt1 and Gtt2, or the two glutaredoxins, Grx1 and Grx2, that also possess glutathione S-transferase activity.
Rai
Rajendra
R
Department of Molecular Sciences, University of Tennessee, Memphis, TN 38163, USA.
Cooper
Terrance G
TG
D054477:Glutaredoxins; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000633:toxicity; D019216:Metals, Heavy / Q000378:metabolism* / Q000633:toxicity; D010088:Oxidoreductases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
D054477:Glutaredoxins; D019216:Metals, Heavy; D011328:Prions; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae; D005982:Glutathione Transferase