Review
Zinc finger proteins: new insights into structural and functional diversity

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Abstract

Zinc finger proteins are among the most abundant proteins in eukaryotic genomes. Their functions are extraordinarily diverse and include DNA recognition, RNA packaging, transcriptional activation, regulation of apoptosis, protein folding and assembly, and lipid binding. Zinc finger structures are as diverse as their functions. Structures have recently been reported for many new zinc finger domains with novel topologies, providing important insights into structure/function relationships. In addition, new structural studies of proteins containing the classical Cys2His2 zinc finger motif have led to novel insights into mechanisms of DNA binding and to a better understanding of their broader functions in transcriptional regulation.

Introduction

The zinc finger was first recognized 15 years ago as a repeated zinc-binding motif, containing conserved cysteine and histidine ligands, in Xenopus transcription factor IIIA (TFIIIA) 1. Since that time, numerous other zinc-binding motifs have been identified and designated as zinc fingers. These vary widely in structure, as well as in function, which ranges from DNA or RNA binding to protein–protein interactions and membrane association. We now recognize the classical Cys2His2 zinc finger as the first member of a rapidly expanding family of zinc-binding modules. For the purposes of this review, we define a zinc finger to be any small, functional, independently folded domain that requires coordination of one or more zinc ions to stabilize its structure. In this article, we review recent advances in the structural biology of zinc finger proteins. We focus first on zinc fingers that function by binding nucleic acids or otherwise participate in transcriptional or translational processes. However, for the sake of completeness, we extend the discussion to encompass other novel zinc finger domains whose structures have been elucidated recently, even though their functions do not involve interactions with nucleic acids. A notable omission from this review is the zinc fingers from nuclear hormone receptors, which are reviewed in another article in this issue (see the review by Rastinejad, pp 33–38).

Section snippets

DNA binding by Cys2His2 zinc fingers

Proteins containing the classical Cys2His2 zinc finger are amongst the most abundant in eukaryotic genomes. Many of these proteins are transcription factors that function by recognition of specific DNA sequences. Since the structure of a single zinc finger was first reported in 1989 2 (Fig. 1a), the structures of numerous complexes with DNA have been described, beginning with that of Zif268 3. These structures have established the invariance of the ββα framework of the Cys2His2 zinc finger

Zinc finger engineering

In recent years, much effort has been focused on the design of novel Cys2His2 zinc finger proteins that can specifically target unique binding sites within the human genome. Such ‘designer’ zinc fingers have important applications as probes and may ultimately prove valuable for human gene therapy. As a thorough review of recent progress in zinc finger engineering has been presented recently 13, this topic will be discussed only briefly. One of the current challenges in zinc finger protein

Zinc-sensing proteins

Regulatory mechanisms have evolved in all organisms to control the homeostasis of metal ions. The response of mammalian cells to surplus zinc appears to be largely mediated by metallothionein, which acts to chelate and sequester the excess metal from the cellular environment. Metallothionein synthesis is induced by zinc excess and is regulated through the metal-response element (MRE) by the transcription factor MTF-1 (MRE-binding transcription factor 1), which contains six Cys2His2 zinc

A broader function for TFIIIA-type ββα folds

Although the majority of the Cys2His2 zinc finger proteins identified to date are implicated in nucleic acid binding, it is becoming increasingly clear that some members of this superfamily function by mediating protein–protein interactions. For example, the zinc finger protein Ikaros, which plays a crucial role in lymphoid differentiation, forms homodimers through the association of the two C-terminal Cys2His2 zinc finger motifs 19. The Ikaros-related protein Aiolos both homodimerizes and

Nucleic acid recognition by other zinc finger motifs

The DM motif is a zinc-dependent DNA-binding domain found in a number of transcription factors that regulate sexual differentiation. A recent NMR structure revealed that the DM motif is a novel zinc finger containing intertwined CCHC and HCCC ligands 26radical dot. The two zinc-binding sites stabilize a compact globular domain that contains two α helices. The second helix extends into an unstructured C-terminal tail that functions as a nascent DNA-recognition helix, folding into a helical structure upon

Zinc fingers in RNA polymerase

The crystal structure of yeast RNA polymerase II reveals six zinc-binding proteins, several of which appear to meet the criteria for classification as zinc fingers 31. Subunit nine (Rpb9) forms two distinct zinc-binding domains separated by a long linker: the smaller C-terminal zinc-binding module has previously been shown to fold independently into a zinc ribbon motif similar to that observed in transcription factor IIS (TFIIS) 32., 33.. Subunit Rpb12 appears to have a similar zinc ribbon

Conclusions

Recent structural studies of zinc finger proteins have shed new insights into their extraordinary diversity of structure and function. It is chastening to realize, however, that of the large number of putative zinc finger motifs that have been identified, only a handful have been characterized structurally. Although some of these will undoubtedly prove to have novel folds, it is notable that recently determined structures of several previously uncharacterized zinc finger domains show that they

Update

The solution structure of the plant homeodomain (PHD) motif has been reported recently 57, 58.. It folds into an interleaved zinc finger domain that binds two zinc atoms. The zinc-binding core is similar in structure to that of the FYVE and RING domains. The PHD motif is found in both single and multiple copies within transcriptional control proteins. Mutations within the PHD motif are associated with developmental disorders, such as Williams–Beuren syndrome, X-linked mental retardation and

Acknowledgements

JHL and BML are supported by fellowships from the National Institutes of Health (NIH). Research on zinc finger proteins is supported by NIH grant GM36643 to PEW.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot. of outstanding interest

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