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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-13109

Chen, X; Hua, H; Balamurugan, K; Kong, X; Zhang, L; George, G N; Georgiev, O; Schaffner, W; Giedroc, D P (2008). Copper sensing function of Drosophila metal-responsive transcription factor-1 is mediated by a tetranuclear Cu(I) cluster. Nucleic Acids Research, 36(9):3128-3138.

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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 ace1∆ 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).


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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Date:May 2008
Deposited On:15 Feb 2009 11:40
Last Modified:05 Apr 2016 12:58
Publisher:Oxford University Press
Funders:US National Institutes of Health (GM042569) , Robert A. Welch Foundation (A-1295), Swiss National Science Foundation (3100-064139), Kanton Zurich, European Union (GENINTEG project ‘Mechanisms of Gene Integration’ LSHG-CT-2003-503303)
Additional Information:Full final text Oxford Journal
Publisher DOI:10.1093/nar/gkn103
PubMed ID:18411209

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