The Krüppel-associated box-A (KRAB-A) domain of zinc finger proteins mediates transcriptional repression.

Abstract

We have previously reported the cloning, sequencing, and partial characterization of Kid-i, a zinc finger-encoding cDNA from the rat kidney. A limited number of structural motifs have been described for eukaryotic transcription factors. A common motif is the zinc finger structure, which is highly conserved and found in many different species (1). Though the crystal structure of a cocrystal between the three zinc fingers of zif-268 (Egr-i) and their binding site has been elucidated (2), little is known about the interaction between zinc fingers and DNA and how these protein-DNA interactions are involved in the regulation of transcription.Approximately one-third of all zinc finger proteins contain an evolutionarily conserved region of about 75 amino acids at their NH2 terminus-the Krippel-associated box (KRAB), a sequence motif of hitherto unknown function. Similar to regions found in a subset of homeodomain proteins (the paired box and POU domain), the KRAB domain is rich in charged amino acids (3). Because of the potential a-helical structure of KRAB domains, it has been proposed that this domain mediates protein-protein interactions and functions as a transcriptional regulatory domain (3), but this hypothesis has not been previously tested.

A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas

“…The KRAB domain is a highly charged 75 amino acid motif that de®nes a large sub-family of Cys2His2-type (KruÈ ppel-type) zinc ®nger DNA binding proteins, such as KOX1, which act as potent transcriptional repressors (Margolin et al, 1994;Pengue et al, 1994;Witzgall et al, 1994). It can be further divided into two sub-domains, A and B (see Figure 2), which are predicted to fold into two amphipathic helices.…”

TIPUH1 encodes a novel KRAB zinc-finger protein highly expressed in human hepatocellular carcinomas

“…Kruppel-associated box/Cys2-His2 zinc-finger proteins (KZFP) constitute the single largest class of potential regulators of gene expression (Mark et al, 1999). The KRAB domain is a conserved motif at the N-terminus of a large number of zinc-finger proteins, comprising a 75-amino-acid stretch that can be divided into the KRAB-A domain, a 45-aa-long minimal repression module, and the KRAB-B domain (Witzgall et al, 1994). TIPUH1 protein contains only the KRAB-A domain that, as in other KZFPs, is located in its N-terminal region.…”

“…Kruppel-associated box-containing proteins function as transcriptional repressors when tethered to template DNAs through their DNA-binding domains (Witzgall et al, 1994;Collins et al, 2001;Looman et al, 2002). This transcriptional silencing is thought to be mediate via interaction of the KRAB box with the ubiquitous corepressor TIF1b (Nielsen et al, 1999;Collins et al, 2001).…”

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

“…The Kruppel associated box (KRAB) is a protein domain of approximately 75 amino-acid residues and has been shown to act as a potent DNA-bindingdependent transcriptional repressor (Margolin et al, 1994;Witzgall et al, 1994;Pengue et al, 1995;Vissing et al, 1995) that inhibits the transcriptional machinery and/or alters the chromatin structure (Kingston et al, 1996;Moosmann et al, 1997). Approximately, onethird of the zinc-finger proteins of the Kruppel Cys 2 His 2 -type contain KRAB domains at their amino termini (Bellefroid et al, 1991).…”