Structural and Functional Evolution of Interacting C 2 H 2 Zinc Finger Proteins

The canonical model for multiple C 2 H 2 zinc fingers are independently folded tethered “beads on a string”. Using a structural and genomic approach, we have identified a new interacting “two‐finger” class of C 2 H 2 zinc fingers from diverse group of organisms (fungi to humans). Two interacting zinc finger structures have been solved to date: 1) an X‐ray structure of the five‐finger DNA binding domain of the human GLI protein bound to DNA, in which the two N‐terminal fingers are interacting, and 2) our recent NMR structure of an isolated two‐finger domain within the Zap1 protein from S. cerevisiae . Both two‐finger proteins form similar structures that are stabilized by two key Trp residues at conserved residue positions, which are not part of the canonical consensus for the general C 2 H 2 zinc finger family. These Trp residues contribute to an extended hydrophobic core that links the respective “canonical” cores of the individual fingers. Evidence is provided that, for each two‐finger protein, one finger has a defined functional role, while the other finger has a defined regulatory role. Phylogenetic studies further suggest that one fundamental unit of evolution for these two‐finger proteins is the division of labor into distinct functional (C‐terminal finger) and regulatory (N‐terminal finger) roles.