The Krüppel associated box (KRAB) domain is a category of transcriptional repression domains present in approximately 400 human

zinc finger protein A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

-based

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s (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 An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...

helices. The most prominent interacting protein is called

TRIM28 Tripartite motif-containing 28 (TRIM28), also known as transcriptional intermediary factor 1β (TIF1β) and KAP1 (KRAB-associated protein-1), is a protein that in humans is encoded by the ''TRIM28'' gene. Function The protein encoded by this ge ...

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.

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 Zinc finger protein 10 is a protein that in humans is encoded by the ''ZNF10'' gene. Function The protein encoded by this gene contains a C2H2 zinc finger, and has been shown to function as a transcriptional repressor. The Kruppel-associated b ...

coined heptad repeat of leucines (also known as a

leucine zipper A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...

). Later, this domain was named in association with the C2H2-Zinc finger proteins Krüppel associated box (KRAB). The KRAB domain is confined to genomes from

tetrapod Tetrapods (; ) are four-limbed vertebrate animals constituting the superclass Tetrapoda (). It includes extant and extinct amphibians, sauropsids ( reptiles, including dinosaurs and therefore birds) and synapsids ( pelycosaurs, extinct t ...

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. The KRAB domain presents one of the strongest repressors in the human genome. 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.

Examples

Human genes encoding KRAB-ZFPs include KOX1/

, KOX8/ZNF708,

ZNF43 Zinc finger protein 43 is a protein that in humans is encoded by the ''ZNF43'' gene. Function This gene belongs to the C2H2-type zinc finger gene family. The zinc finger proteins are involved in gene regulation and development, and are quite c ...

, ZNF184, ZNF91, HPF4, HTF10 and HTF34.

Evolution

Examples

References

Further reading