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).^[1] The KRAB domain typically consists of about 75 amino acid residues, while the minimal repression module is approximately 45 amino acid residues.^[2] 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,^[3] cloned as KAP1^[4] and TIF1-beta.^[5] Substitutions for the conserved residues abolish repression.

Krüppel Associated Box
KRAB domain
Identifiers
Symbol	KRAB
Pfam	PF01352
InterPro	IPR001909
SMART	SM00349
PROSITE	PS50805
SCOP2	1v65 / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1v65A:8-48

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.^[6]

Evolution

The KRAB domain had initially been identified in 1988 as a periodic array of leucine residues separated by six amino acids 5’ to the zinc finger region of KOX1/ZNF10^[7] coined heptad repeat of leucines (also known as a leucine zipper).^[8] Later, this domain was named in association with the C2H2-Zinc finger proteins Krüppel associated box (KRAB).^[9][10] The KRAB domain is confined to genomes from tetrapod organisms. The KRAB containing C2H2-ZNF genes constitute the largest sub-family of zinc finger genes. More than half of the C2H2-ZNF genes are associated with a KRAB domain in the human genome. They are more prone to clustering and are found in large clusters on the human genome.^[11]

The KRAB domain presents one of the strongest repressors in the human genome.^[2] Once the KRAB domain was fused to the tetracycline repressor (TetR), the TetR-KRAB fusion proteins were the first engineered drug-inducible repressor that worked in mammalian cells.^[3] Two distinct types of KRAB A domains can be structurally and functionally distinguished. Ancestral KRAB A domains present in human PDRM9 proteins are even evolutionary conserved in mussel genomes. Modern KRAB A domain sequences are found in coelacanth latimeria chalumnae and in Lungfish genomes.^[12]

Examples

Human genes encoding KRAB-ZFPs include KOX1/ZNF10, KOX8/ZNF708, ZNF43, ZNF184, ZNF91, HPF4, HTF10 and HTF34.