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Copper sensing function of Drosophila metal-responsive transcription factor-1 is mediated by a tetranuclear Cu(I) cluster

Chen, Xiaohua ; Hua, Haiqing ; Balamurugan, Kuppusamy ; Kong, Xiangming ; Zhang, Limei ; George, Graham N. ; Georgiev, Oleg ; Schaffner, Walter ; Giedroc, David P.

In: Nucleic Acids Research, 2008, vol. 36, no. 9, p. 3128-3138

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    Title
    • Copper sensing function of Drosophila metal-responsive transcription factor-1 is mediated by a tetranuclear Cu(I) cluster
    Author
    • Chen, Xiaohua. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Hua, Haiqing. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Balamurugan, Kuppusamy. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Kong, Xiangming. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Zhang, Limei. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • George, Graham N.. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Georgiev, Oleg. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Schaffner, Walter. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    • Giedroc, David P.. Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA, Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, 8057 Zurich, Switzerland, Department of Geological Sciences, University of Saskatchewan, Saskatoon, S7N 5E2, Canada and Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Nucleic Acids Research, 2008, vol. 36, no. 9, p. 3128-3138. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:293521
    Summary
    Drosophila melanogaster MTF-1 (dMTF-1) is a copper-responsive transcriptional activator that mediates resistance to Cu, as well as Zn and Cd. Here, we characterize a novel cysteine-rich domain which is crucial for sensing excess intracellular copper by dMTF-1. Transgenic flies expressing mutant dMTF-1 containing alanine substitutions of two, four or six cysteine residues within the sequence 547CNCTNCKCDQTKSCHGGDC565 are significantly or completely impaired in their ability to protect flies from copper toxicity and fail to up-regulate MtnA (metallothionein) expression in response to excess Cu. In contrast, these flies exhibit wild-type survival in response to copper deprivation thus revealing that the cysteine cluster domain is required only for sensing Cu load by dMTF-1. Parallel studies show that the isolated cysteine cluster domain is required to protect a copper-sensitive S. cerevisiae ace1Δ strain from copper toxicity. Cu(I) ligation by a Cys-rich domain peptide fragment drives the cooperative assembly of a polydentate [Cu4-S6] cage structure, characterized by a core of trigonally S3 coordinated Cu(I) ions bound by bridging thiolate ligands. While reminiscent of Cu4-L6 (L = ligand) tetranuclear clusters in copper regulatory transcription factors of yeast, the absence of significant sequence homology is consistent with convergent evolution of a sensing strategy particularly well suited for Cu(I)