zincfingers

Zinc fingers are small protein structural motifs that coordinate one or more zinc ions to stabilize folds capable of interacting with nucleic acids, proteins, or small molecules. The best-characterized class is the C2H2 zinc finger, in which a zinc ion is coordinated by two cysteines and two histidines. Each finger is typically 28 to 30 amino acids long and folds into a beta-hairpin and an alpha-helix; the recognition helix positions itself in the DNA major groove to contact bases. Multiple fingers arranged in tandem can recognize longer DNA sequences, with specific residues at defined positions making base contacts that determine sequence specificity. Beyond DNA binding, zinc fingers can mediate RNA interactions or protein–protein contacts, and large families of zinc finger proteins function as transcription factors regulating development, differentiation, or metabolism. Other zinc finger subtypes exist, including C4 motifs in some nuclear receptors and less common patterns such as C2HC and treble-clef arrangements.

Zinc finger domains have been leveraged as tools for genome engineering. In the late 1990s and early 2000s, researchers constructed zinc finger nucleases (ZFNs) by fusing engineered zinc finger arrays to the FokI nuclease, enabling targeted DNA double-strand breaks. ZFNs and related engineered zinc finger platforms allowed targeted gene disruption, correction, or insertion in various cell types, contributing to the early growth of genome editing. However, their design can be complex and context-dependent, with potential off-target activity and variable performance across targets. As a result, newer platforms such as transcription activator-like effector nucleases (TALENs) and CRISPR-Cas systems have become more prevalent, though zinc finger approaches remain of historical importance and are still used in specialized applications and protein engineering research.