Zinc fingers: Gilt by association

Abstract

A major focus of molecular biology is the identification of mechanisms by which eukaryotic gene transcription is regulated in a precise temporal and spatial fashion. The identification of transcriptional factors with the ability to recognize and bind to specific DNA sequences has provided important clues to elucidating these mechanisms. X-ray crystallographic analysis of prokaryotic DNA binding proteins such as lambda repressor and cro revealed a common helix-turn-helix motif responsible for their interaction with DNA(Pabo and Sauer, Ann. Rev. Biothem. 53, 293-321, 1984). The notion that this structure is universally used for specific DNA interaction was challenged by Klug’s recognition of a new DNA binding motif in Xenopus laevis transcription factor TFIIIA: the zinc finger (Miller et al., EMBO J. 4, 1609-1614, 1985). Although originally recognized in an RNA polymerase Ill transcription factor, recent analysis has revealed potential metal binding fingers as a surprisingly common structure in a variety of nucleic acid binding proteins (for review see Berg, Science 232,485-487, 1986), including factors likely to influence polymerase II transcription. Finger Structure and Metal Binding Isolation and comparison of cDNAs encoding potential finger proteins indicate the existence of at least two classes of proteins with specific nucleic acid recognition capabilities. These classes are characterized according to the number and position of the cysteine and histidine residues available for zinc coordination (see table). The &HZ class is typified by TFIIIA and is comprised of proteins containing, as the basic structural unit, pairs of cysteines and histidines separated by a loop of twelve amino acids. Although most easily visualized as a finger of amino acids anchored by zinc and projecting from the surface of the protein (see figure, part A), an alternate view, inferred from structures of known metalloproteins, suggests the more complex model depicted in part B of the figure (Berg, PNAS 85, 99-102, 1988). In the C2H2 proteins identified, the finger motif is tandemly repeated a minimum of two times with a 7 to 8 amino acid linker separating the units (the H/C link). In contrast to the C2H2 group, the C, proteins have a variable number of conserved cysteines available for metal chelation. For the yeast transcriptional factors, such as GAL4, the putative finger region exists as a cluster of six invariant cysteines (C, family), whereas the steroid receptors contain two apparently unrelated fingers encoded by separate exons (Huckaby et al., PNAS 84, 8380-8384, 1987) with four (C,) and five (C,) conserved Minireview