The most significant event in zinc biology of recent years has been the discovery of the "zinc finger" domains as specific tertiary structure elements of DNA-binding proteins and the demonstration of the dominant role these structures are playing in the regulation of eukaryotic gene expression. It revealed novel roles of zinc in genetic information control and widened thus very dramatically the scope of action of this trace element.
The zinc finger concept made its stage debut in the here reproduced 1985 paper of Miller, McLachlan, and Klug on the transcription factor III A (TFIIIA) of Xenopus laevis oocytes [1]. In their visionary article these authors suggested that this protein, which controls transcription of the 5S rRNA genes, is composed of a row of nine homologous mini-domains folded around a central zinc ion, and that these modules, pictorially designated as "zinc fingers", make the contacts to the DNA. The basis for the proposal were fragmentation studies by the authors, the already available knowledge that zinc was needed for DNA binding [2], and the timely apperception that the sequence of TFIIIA features a nine-fold repeat of the consensus motif -Tyr, Phe -X -Cys -X 2-4 -Cys -X 3 -Phe -X 5 -Leu -X 2 -His -X 3,4 -His -X 2-6 -(where X is a variable residue). From the invariance of the two cysteines and histidines in the segment and from the stoichiometric amounts of zinc binding to the protein they inferred that these residues serve as zinc binding ligands and that by their coordination to the metal ion each polypeptide segment is crosslinked to form a separate loop and that these loops are binding in file to the target sites in the control region of the 5S rRNA genes and thereby are regulating their transcription.
The same repetitive Cys 2 His 2 sequence motif was quickly also recognised in a range of other transcription factors [3,4] and has since turned up in hundreds of additional proteins, collectively designated as "zinc finger proteins." Many of them are active in growth, in differentiation and in the regulation of cell fate in embryogenesis [4]. The classical Cys 2 His 2 finger is indeed one of the most frequent domain structures of eukaryotic DNA-binding proteins [5]. In the human genome it is with a total number of approximately 4500 Cys 2 His 2 domains the by far most abundant single structural motif [6,7].
The predicted folding of the segments [5] and the modular organisation of the Cys 2 His 2 finger proteins was speedily confirmed by spectroscopic studies and spatial structure analysis [8,9]. Both 2D NMR and X-ray studies revealed that the fingers have a common structural framework composed of a small antiparallel -sheet and a