C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family of Higher Eukaryotic Transcription Factors

Abstract

The emergence of whole-genome assays has initiated numerous genome-wide studies of transcription factor localizations at genomic regulatory elements (enhancers, promoters, silencers, and insulators), as well as facilitated the uncovering of some of the key principles of chromosomal organization. However, the proteins involved in the formation and maintenance of the chromosomal architecture and the organization of regulatory domains remain insufficiently studied. This review attempts to collate the available data on the abundant but still poorly understood family of proteins with clusters of the C2H2 zinc finger domains. One of the best known proteins of this family is a well conserved protein known as CTCF, which plays a key role in the establishment of the chromosomal architecture in vertebrates. The distinctive features of C2H2 zinc finger proteins include strong and specific binding to a long and unique DNA recognition target sequence and rapid expansion within various animal taxa during evolution. The reviewed data support a proposed model according to which many of the C2H2 proteins have functions that are similar to those of the CTCF in the organization of the chromatin architecture.

Keywords: CTCF; KRAB domain; SCAN domain; ZAD; architectural proteins; transcription factors.

Fig. 1

A model of the site-specific DNA recognition by C2H2 zinc finger domains. (A) The crystal structure of three zinc fingers of the Zif268 protein bound to DNA [20]. The amino acids involved in the site-specific DNA recognition are color-coded: –1 – green, +2 – blue, +3 – red, and +6 – purple. (B) A model of the site-specific DNA recognition by α-helical amino acids (adapted from [24]).

Fig. 2

Relative abundance of different variants of C2H2 proteins in various higher eukaryotes: human (Homo sapiens), mouse (Mus musculus), wild bull (Bos taurus), chicken (Gallus gallus), zebrafish (Danio rerio), fruit fly (Drosophila melanogaster), anopheles mosquito (Anopheles darlingi), and frog (Xenopus laevis). Data were obtained from the Uniprot database.

Fig. 3

Comparison of the structures and properties of the Drosophila and human CTCF proteins. (A) The domain structures of the Drosophila and human CTCF proteins. The domains involved in the site-specific DNA recognition and the protein-protein interactions are represented by thin horizontal lines. Drosophila and human [46] CTCFs have similar consensus recognition sites. (B) The mechanism of the long-distance genomic interactions mediated by CTCF and cohesins.

Fig. 4

The structure and properties of the KRAB domain. (A) A typical domain structure of the KRAB C2H2 proteins. (B) The NMR structure of KRAB A: 5 mammalian conserved aa are shown in green (DV in positions 6 and 7, and MLE in positions 36–38); they are essential for the KAP-1 recruitment [PDB 1V65]. (C) The mechanism of KAP 1 recruitment and the subsequent formation of the repressive complex.

Fig. 5

The structure and properties of the SCAN domain. (A) A typical domain structure of the SCAN C2H2 and SCAN KRAB C2H2 proteins. (B) The crystal structure of a SCAN domain dimer from the Zfp206 protein [110].

Fig. 6

The structure and properties of the ZAD. (A) A typical domain structure of ZAD C2H2 proteins. (B) The crystal structure of a ZAD dimer from the Grau protein [117].