title: A conserved cysteine cluster, essential for transcriptional activity, mediates homodimerization of human metal-responsive transcription factor-1 (MTF-1).
abstract: Metal-responsive transcription factor-1 (MTF-1) is a zinc finger protein that activates transcription in response to heavy metals such as Zn(II), Cd(II) and Cu(I) and is also involved in the response to hypoxia and oxidative stress. MTF-1 recognizes a specific DNA sequence motif termed the metal response element (MRE), located in the promoter/enhancer region of its target genes. The functional domains of MTF-1 include, besides the DNA-binding and activation domains and signals for subcellular localization (NLS and NES), a cysteine cluster 632CQCQCAC638 located near the C-terminus. Here we show that this cysteine cluster mediates homodimerization of human MTF-1, and that dimer formation in vivo is important for basal and especially metal-induced transcriptional activity. Neither nuclear translocation nor DNA binding is impaired in a mutant protein in which these cysteines are replaced by alanines. Although zinc supplementation induces MTF-1 dependent transcription it does not per se enhance dimerization, implying that actual zinc sensing is mediated by another domain. By contrast copper, which on its own activates MTF-1 only weakly in the cell lines tested, stabilizes the dimer by inducing intermolecular disulfide bond formation and synergizes with zinc to boost MTF-1 dependent transcription.
authors: Institute of Molecular Life Sciences, Universität Zürich, Zürich, Switzerland.
authors: Viola
authors: V
authors: Günther
authors: Alisa M
authors: AM
authors: Davis
authors: Oleg
authors: O
authors: Georgiev
authors: Walter
authors: W
authors: Schaffner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015032:Zinc / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000097809:Transcription Factor MTF-1
chemical_list: D003300:Copper; D003545:Cysteine; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D015032:Zinc; D050880:p300-CBP Transcription Factors; D000097809:Transcription Factor MTF-1