Krüppel associated box explained

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.

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. 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.

Further reading

Notes and References

  1. Huntley S, Baggott DM, Hamilton AT, Tran-Gyamfi M, Yang S, Kim J, Gordon L, Branscomb E, Stubbs L . A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors . Genome Res. . 16 . 5 . 669–77 . May 2006 . 16606702 . 1457042 . 10.1101/gr.4842106 .
  2. Margolin JF, Friedman JR, Meyer WK, Vissing H, Thiesen HJ, Rauscher FJ . Krüppel-associated boxes are potent transcriptional repression domains . Proc. Natl. Acad. Sci. U.S.A. . 91 . 10 . 4509–13 . May 1994 . 8183939 . 43815 . 10.1073/pnas.91.10.4509 . 1994PNAS...91.4509M . free .
  3. Deuschle U, Meyer WK, Thiesen HJ . Tetracycline-reversible silencing of eukaryotic promoters . Mol. Cell. Biol. . 15 . 4 . 1907–14 . April 1995 . 7891684 . 230416 . 10.1128/mcb.15.4.1907.
  4. Friedman JR, Fredericks WJ, Jensen DE, Speicher DW, Huang XP, Neilson EG, Rauscher FJ . KAP-1, a novel corepressor for the highly conserved KRAB repression domain . Genes Dev. . 10 . 16 . 2067–78 . August 1996 . 8769649 . 10.1101/gad.10.16.2067 . free .
  5. Moosmann P, Georgiev O, Le Douarin B, Bourquin JP, Schaffner W . Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1 . Nucleic Acids Res. . 24 . 24 . 4859–67 . December 1996 . 9016654 . 146346 . 10.1093/nar/24.24.4859 .
  6. Jensen . Trine I. . Mikkelsen . Nanna S. . Gao . Zongliang . Foßelteder . Johannes . Pabst . Gabriel . Axelgaard . Esben . Laustsen . Anders . König . Saskia . Reinisch . Andreas . Bak . Rasmus O. . 2021-08-18 . Targeted regulation of transcription in primary cells using CRISPRa and CRISPRi . Genome Research . 31 . 11 . 2120–2130 . 10.1101/gr.275607.121 . 1549-5469 . 34407984 . 8559706.
  7. Book: Basel Institute for Immunology . Annual Report . 1988 . Basel . 53 . 0301-3782 . 1793356 .
  8. . Multiple genes encoding zinc finger domains are expressed in human T cells . New Biol. . 2 . 4 . 363–74 . April 1990 . 2288909 .
  9. Bellefroid EJ, Poncelet DA, Lecocq PJ, Revelant O, Martial JA . The evolutionarily conserved Krüppel-associated box domain defines a subfamily of eukaryotic multifingered proteins . Proc. Natl. Acad. Sci. U.S.A. . 88 . 9 . 3608–12 . May 1991 . 2023909 . 51501 . 10.1073/pnas.88.9.3608 . 1991PNAS...88.3608B . free .
  10. Thiesen HJ, Bellefroid E, Revelant O, Martial JA . Conserved KRAB protein domain identified upstream from the zinc finger region of Kox 8 . Nucleic Acids Res. . 19 . 14 . 3996 . July 1991 . 1861988 . 328495 . 10.1093/nar/19.14.3996 .
  11. Rousseau-Merck MF, Koczan D, Legrand I, Möller S, Autran S, Thiesen HJ . The KOX zinc finger genes: genome wide mapping of 368 ZNF PAC clones with zinc finger gene clusters predominantly in 23 chromosomal loci are confirmed by human sequences annotated in EnsEMBL . Cytogenet. Genome Res. . 98 . 2–3 . 147–53 . 2002 . 12697996 . 10.1159/000069802 . 29964545 .
  12. Lorenz P, Steinbeck F, Krause L, Thiesen HJ . The KRAB Domain of ZNF10 Guides the Identification of Specific Amino Acids That Transform the Ancestral KRAB-A-Related Domain Present in Human PRDM9 into a Canonical Modern KRAB-A Domain . International Journal of Molecular Sciences . 23 . 3 . 2022-01-19 . 1422-0067 . 10.3390/ijms23031072 . 8835667 . 35162997 . 1072 . free.

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