Cys2His2Zinc Finger Proteins

Abstract

AbstractThe Cys2His2(C2H2) zinc finger is one of the simplest independently folded structural domains known, yet the number of proteins with distinct and complex functions that contain the motif is too large to count. The domain consists of a small antiparallel β‐sheet and a single helix that contribute two cysteine and two histidine ligands respectively to coordinate a central Zn(II) ion in a nearly perfect tetrahedral geometry. The C2H2 zinc finger is one of the major DNA binding motifs in eukaryotic transcription factors, and probably the most common protein motif in the human genome. DNA sequence specificity is achieved through residue side‐chain contacts to DNA bases that occur at preferential residue positions located in the N‐terminal region of the zinc finger helix (‘fingertip’) that reside primarily on one surface of the domain. Functional specificity and diversity of C2H2 zinc finger proteins are, paradoxically, both achieved through tandem repeats of the motif separated by short, conserved peptide linkers, where each individual finger is capable of recognizing a distinct DNA subsite. Diversity of the C2H2 motif extends beyond DNA recognition to protein–RNA and protein–protein interactions, although these functions are not well understood. Since the first reported structure of a single finger almost 15 years ago, over 40 C2H2 zinc finger structures have been reported both free and bound to DNA. Detailed molecular aspects of C2H2 zinc finger structure, function, and metal binding are examined.