Zinc finger

The term zinc finger was originally coined to describe the finger-like appearance of a hypothesized structure from the African clawed frog (Xenopus laevis) transcription factor IIIA.

Unlike many other clearly defined supersecondary structures such as Greek keys or β hairpins, there are a number of types of zinc fingers, each with a unique three-dimensional architecture.

Since their original discovery and the elucidation of their structure, these interaction modules have proven ubiquitous in the biological world and may be found in 3% of the genes of the human genome.

Zinc fingers were first identified in a study of transcription in the African clawed frog, Xenopus laevis in the laboratory of Aaron Klug.

Extended x-ray absorption fine structure confirmed the identity of the zinc ligands: two cysteines and two histidines.

[4] More recent work in the characterization of proteins in various organisms has revealed the importance of zinc ions in polypeptide stabilization.

[12] Zinc finger (Znf) domains are relatively small protein motifs that contain multiple finger-like protrusions that make tandem contacts with their target molecule.

They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein, and/or lipid substrates.

[19] The following table[19] shows the different structures and their key features: The Cys2His2-like fold group (C2H2) is by far the best-characterized class of zinc fingers, and is common in mammalian transcription factors.

Such domains adopt a simple ββα fold and have the amino acid sequence motif:[20] This class of zinc fingers can have a variety of functions such as binding RNA and mediating protein-protein interactions, but is best known for its role in sequence-specific DNA-binding proteins such as Zif268 (Egr1).

[23] Fusions between engineered zinc finger arrays and protein domains that cleave or otherwise modify DNA can also be used to target those activities to desired genomic loci.

Arrays with 6 zinc finger motifs are particularly attractive because they bind a target site that is long enough to have a good chance of being unique in a mammalian genome.

Such zinc finger-FokI fusions have become useful reagents for manipulating genomes of many higher organisms including Drosophila melanogaster, Caenorhabditis elegans, tobacco, corn,[25] zebrafish,[26] various types of mammalian cells,[27] and rats.

[28] Targeting a double-strand break to a desired genomic locus can be used to introduce frame-shift mutations into the coding sequence of a gene due to the error-prone nature of the non-homologous DNA repair pathway.

An ongoing clinical trial is evaluating Zinc finger nucleases that disrupt the CCR5 gene in CD4+ human T-cells as a potential treatment for HIV/AIDS.

[30] The structure of this protein bound to DNA was solved in 1991[9] and stimulated a great deal of research into engineered zinc finger arrays.

A recent study demonstrated that a high proportion of 3-finger zinc finger arrays generated by modular assembly fail to bind their intended target with sufficient affinity in a bacterial two-hybrid assay and fail to function as zinc finger nucleases, but the success rate was somewhat higher when sites of the form GNNGNNGNN were targeted.

A promising new method to select novel 3-finger zinc finger arrays utilizes a bacterial two-hybrid system and has been dubbed "OPEN" by its creators.