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Gene Review

ZAP1  -  Zap1p

Saccharomyces cerevisiae S288c

Synonyms: J1145, YJL056C, Zinc-responsive transcriptional regulator ZAP1
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Disease relevance of ZAP1


High impact information on ZAP1

  • The Zap1 transcriptional activator also acts as a repressor by binding downstream of the TATA box in ZRT2 [2].
  • The zinc-responsive transcriptional activator Zap1 regulates the expression of both high- and low-affinity zinc uptake permeases encoded by the ZRT1 and ZRT2 genes [2].
  • Zap1 mediates this response by binding to zinc-responsive elements (ZREs) located within the promoter regions of each gene [2].
  • ZRT3 is a Zap1p-regulated gene whose transcription increases in low zinc [3].
  • We describe here a new component of zinc homeostasis, vacuolar zinc storage, that is also regulated by Zap1p [3].

Biological context of ZAP1

  • ZAP1 encodes a 93-kDa protein with sequence similarity to transcriptional activators; the C-terminal 174 amino acids contains five C2H2 zinc finger domains, and the N terminus (residues 1 to 706) has two potential acidic activation domains [4].
  • Regulation of zinc homeostasis in yeast by binding of the ZAP1 transcriptional activator to zinc-responsive promoter elements [5].
  • These studies demonstrate that ZAP1 plays a direct role in controlling zinc-responsive gene expression in yeast by binding to zinc-responsive elements in the promoters of genes that it regulates [5].
  • We also demonstrate that ZREs are DNA binding sites for ZAP1 [5].
  • All but YEF3B were shown through reporter gene assays to be controlled by a master regulator of zinc homeostasis now known to be encoded by ZAP1 [6].

Anatomical context of ZAP1

  • ZAP1 mutants lacked the flocculence and distended vacuoles characteristic of zinc-deficient cells, suggesting that flocculation and vacuolation serve homeostatic functions in zinc-deficient cells [6].
  • We further investigated substrate specificity and observed that ZmYS1 complemented the growth defect of the zinc uptake-defective yeast mutant zap1 and transported various phytosiderophore-bound metals into oocytes, including zinc, copper, nickel, and, at a lower rate, also manganese and cadmium [7].

Associations of ZAP1 with chemical compounds

  • Taken together, this work demonstrated that the zinc-mediated regulation of ethanolamine kinase and the synthesis of phospholipids via the CDP-ethanolamine branch of the Kennedy pathway were controlled in part by Zap1p [8].
  • On the basis of the above observations, we propose a mechanism for Zap1 transcriptional regulation in which zf1-zf2 interactions stabilize the betabetaalpha folded "repressed state" of the zf2 activation domain in the presence of cellular Zn(II) excess [9].

Regulatory relationships of ZAP1

  • Second, FET4 is regulated by zinc status via the Zap1 transcription factor [10].
  • ZRG17 was previously identified as a zinc-regulated gene controlled by the zinc-responsive Zap1p transcription factor [11].
  • Under zinc-deplete conditions, the positive transcription factor Zap1p stimulates the expression of the DPP1 and PIS1 genes through the cis-acting element UAS(ZRE) [12].
  • Surprisingly, transcription of ZRC1 is induced in zinc-limited cells by the zinc-responsive transcription factor Zap1 [13].
  • The zinc-mediated regulation of EKI1 expression was attenuated in the zap1Delta mutant defective in the zinc-regulated transcription factor Zap1p [8].

Other interactions of ZAP1

  • We used a genetic approach to isolate mutants whose ZRT1 expression is no longer repressed in zinc-replete cells, and a new gene, ZAP1, was identified [4].
  • This regulation was dependent on the UAS(ZRE) in the DPP1 promoter and was mediated by the Zap1p transcriptional activator [14].
  • In this report, we describe the characterization of zinc-responsive elements (ZREs) in the promoters of the ZRT1, ZRT2, and ZAP1 genes [5].
  • We present evidence that FET4 is a physiologically relevant zinc transporter and this provides a rationale for its regulation by Zap1 [10].
  • Direct interactions between Zap1p and putative zinc-responsive elements in the EKI1 promoter were demonstrated by electrophoretic mobility shift assays [8].

Analytical, diagnostic and therapeutic context of ZAP1

  • Second, electrophoretic mobility shift assays and in vitro DNase I footprint analyses indicated that ZAP1 binds to ZREs in a sequence-specific fashion [5].
  • To understand how Zap1 responds to zinc, we performed a functional dissection of the protein [15].
  • Using a combination of DNA microarrays and a computer-assisted analysis of shared motifs in the promoters of similarly regulated genes, we identified 46 genes that are potentially regulated by Zap1p [16].


  1. Expression of ZRC1 coding for suppressor of zinc toxicity is induced by zinc-starvation stress in Zap1-dependent fashion in Saccharomyces cerevisiae. Miyabe, S., Izawa, S., Inoue, Y. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  2. The Zap1 transcriptional activator also acts as a repressor by binding downstream of the TATA box in ZRT2. Bird, A.J., Blankman, E., Stillman, D.J., Eide, D.J., Winge, D.R. EMBO J. (2004) [Pubmed]
  3. Zinc transporters that regulate vacuolar zinc storage in Saccharomyces cerevisiae. MacDiarmid, C.W., Gaither, L.A., Eide, D. EMBO J. (2000) [Pubmed]
  4. Zap1p, a metalloregulatory protein involved in zinc-responsive transcriptional regulation in Saccharomyces cerevisiae. Zhao, H., Eide, D.J. Mol. Cell. Biol. (1997) [Pubmed]
  5. Regulation of zinc homeostasis in yeast by binding of the ZAP1 transcriptional activator to zinc-responsive promoter elements. Zhao, H., Butler, E., Rodgers, J., Spizzo, T., Duesterhoeft, S., Eide, D. J. Biol. Chem. (1998) [Pubmed]
  6. Zinc-regulated genes in Saccharomyces cerevisiae revealed by transposon tagging. Yuan, D.S. Genetics (2000) [Pubmed]
  7. ZmYS1 functions as a proton-coupled symporter for phytosiderophore- and nicotianamine-chelated metals. Schaaf, G., Ludewig, U., Erenoglu, B.E., Mori, S., Kitahara, T., von Wirén, N. J. Biol. Chem. (2004) [Pubmed]
  8. Regulation of the Saccharomyces cerevisiae EKI1-encoded Ethanolamine Kinase by Zinc Depletion. Kersting, M.C., Carman, G.M. J. Biol. Chem. (2006) [Pubmed]
  9. Solution structure of a Zap1 zinc-responsive domain provides insights into metalloregulatory transcriptional repression in Saccharomyces cerevisiae. Wang, Z., Feng, L.S., Matskevich, V., Venkataraman, K., Parasuram, P., Laity, J.H. J. Mol. Biol. (2006) [Pubmed]
  10. Combinatorial control of yeast FET4 gene expression by iron, zinc, and oxygen. Waters, B.M., Eide, D.J. J. Biol. Chem. (2002) [Pubmed]
  11. Heteromeric protein complexes mediate zinc transport into the secretory pathway of eukaryotic cells. Ellis, C.D., Macdiarmid, C.W., Eide, D.J. J. Biol. Chem. (2005) [Pubmed]
  12. Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc depletion. Carman, G.M., Han, G.S. Biochim. Biophys. Acta (2007) [Pubmed]
  13. Induction of the ZRC1 metal tolerance gene in zinc-limited yeast confers resistance to zinc shock. MacDiarmid, C.W., Milanick, M.A., Eide, D.J. J. Biol. Chem. (2003) [Pubmed]
  14. Regulation of the Saccharomyces cerevisiae DPP1-encoded diacylglycerol pyrophosphate phosphatase by zinc. Han, G.S., Johnston, C.N., Chen, X., Athenstaedt, K., Daum, G., Carman, G.M. J. Biol. Chem. (2001) [Pubmed]
  15. A dual role for zinc fingers in both DNA binding and zinc sensing by the Zap1 transcriptional activator. Bird, A.J., Zhao, H., Luo, H., Jensen, L.T., Srinivasan, C., Evans-Galea, M., Winge, D.R., Eide, D.J. EMBO J. (2000) [Pubmed]
  16. Genome-wide characterization of the Zap1p zinc-responsive regulon in yeast. Lyons, T.J., Gasch, A.P., Gaither, L.A., Botstein, D., Brown, P.O., Eide, D.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
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