Krüppel associated box

The Krüppel associated box (KRAB) domain is a category of transcriptional repression domains present in approximately 400 human zinc finger protein-based transcription factors (KRAB zinc finger proteins). The KRAB domain typically consists of about 75 amino acid residues, while the minimal repression module is approximately 45 amino acid residues. It is predicted to function through protein-protein interactions via two amphipathic helices. The most prominent interacting protein is called TRIM28 initially visualized as SMP1, cloned as KAP1 and TIF1-beta. Substitutions for the conserved residues abolish repression.

Over 10 independently encoded KRAB domains have been shown to be effective repressors of transcription, suggesting this activity to be a common property of the domain. KRAB domains can be fused with dCas9 CRISPR tools to form even stronger repressors. While the KRAB domain from KOX1 (ZNF10) was the first to be functionally characterized and widely used in CRISPRi, a systematic screen of 57 human KRAB domains identified the domain from ZIM3 as a significantly more potent repressor. The ZIM3 KRAB domain exhibits stronger recruitment of the co-repressors TRIM28 and HP1α, leading to more complete gene silencing and improved performance in genome-wide screens compared to traditional KOX1-based tools.