Transcription factor zinc-containing

Yeast transcription factor GAL4 contains a binuclear zinc cluster in its DNA-binding domain... 

This sequence is part of the linear polypeptide chain of the entire protein. The sequence may be repeated one or more times in the DNA-binding protein, and the exact order of the amino acids differs in zinc fingers found in different types of DNA-binding proteins. DNA-binding proteins that contain zinc fingers include the transcription factors that bind the respective hormones EtAR, RXR, VDR, and THR (Zhu etaL, 1997). Other transcription factors that contain zinc fingers include iTHlA, Spl (Spl binds to the GC box) (Narayan et ai., 1997), and steroid hormone receptors. 

A wide variety of transcription factors contain the zinc finger motif, including the steroid hormone receptors, such as the estrogen and the glucocorticoid receptor. Other transcription factors that contain zinc finger motifs include Spl and polymerase III transcription factor TFIIIA (part of the basal transcription complex), which has nine zinc finger motifs. 

Zinc(II) seems to be used also to maintain certain specific (tertiary) structures of proteins. A number of proteins that contain Zn(ll) and that regulate the expression of DNA have been discovered in recent years. That is, this protein switches on and off the transcription of DNA, i.e., production of messenger RNA (see Chap. 4). Such a protein is called in general a transcription factor, whether it contains Zn(ll) or not. The transcription factors that contain Zn(ll) are called often zinc-finger protein, because the Zn(ll) here is used to maintain the specific structure of the protein (called finger ) so that it binds to a specific location of a DNA. 

Dimerization of the Ce-zinc cluster transcription factors involves an a-helical coiled coil in the dimerization region. Coiled coils, often called leucine zippers, are also found in a large group of transcription factors that do not contain zinc. The leucine zipper is made up of two a helices in a coiled coil with every seventh residue leucine or some other large hydrophobic residue, such as isoleucine or valine. Leucine zipper transcription factors (b/zip) include factors characterized by heterodimerization, for example Fos and Jun. The a-helical DNA-binding motifs of the heterodimers recognize quite different base sequences and are continous with the a helices of the zipper. 

A considerable number of transcription factors have reactive cysteine residues, which enable them to respond to the redox conditions in the cell. Since cadmium perturbs redox homeostasis, it can affect this class of transcription factors. If cadmium can displace the tetra-coordinate zinc atoms in zinc finger-containing transcription factors, it will affect them as well. Many of the pathways involving activation and inactivation of transcription factors involve kinases and phosphatases, themselves under the intricate control of calcium fluxes. It is therefore no surprise that cadmium will exert effects on the activity of transcription factors, the activation of proto-oncogenes, and thereby on gene expression (Figure 20.8i and i ). 

The requirement for zinc in the regulation of gene expression is exemplified by transcription factor IIIA, which has been shown to contain from two (Hanas et al., 1983) to seven to eleven (Miller et al., 1985) zinc ions bound to a 40K protein molecule. Transcription factor IIIA is obtained from immature Xenopus oocytes in a complex with 5 S RNA, and the protein is required for transcription initiation the apoprotein does not bind to the 5 S RNA gene (Hanas et al, 1983). Uncertainties regarding the stoichiometric requirement for zinc persist, given the report by Shang et al. (1989) that transcription factor IIIA, as either the isolated protein or the 5 S RNA complex, contains two firmly bound zinc ions which are required for transcription activation. 

The first zinc binding motif discovered was that of the eucaryotic transcription factor TFIIIA of Xenopus laevis which contains 9 copies of a Cys2His2-Zinc motif The structure of the binding motif is shown in Fig. 1.4. The central zinc ion serves to pack an a-hehx against a P-sheet and thereby position the a-helix. The recognition of the DNA sequence occurs via this a-helix. 

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