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
SymbolKRAB
PfamPF01352
InterProIPR001909
SMARTSM00349
PROSITEPS50805
SCOP21v65 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1v65A: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]

Examples

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

References
  1. Huntley S, Baggott DM, Hamilton AT, Tran-Gyamfi M, Yang S, Kim J, Gordon L, Branscomb E, Stubbs L (May 2006). "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. doi:10.1101/gr.4842106. PMC 1457042. PMID 16606702.
  2. Margolin JF, Friedman JR, Meyer WK, Vissing H, Thiesen HJ, Rauscher FJ (May 1994). "Krüppel-associated boxes are potent transcriptional repression domains". Proc. Natl. Acad. Sci. U.S.A. 91 (10): 4509–13. Bibcode:1994PNAS...91.4509M. doi:10.1073/pnas.91.10.4509. PMC 43815. PMID 8183939.
  3. Deuschle U, Meyer WK, Thiesen HJ (April 1995). "Tetracycline-reversible silencing of eukaryotic promoters". Mol. Cell. Biol. 15 (4): 1907–14. doi:10.1128/mcb.15.4.1907. PMC 230416. PMID 7891684.
  4. Friedman JR, Fredericks WJ, Jensen DE, Speicher DW, Huang XP, Neilson EG, Rauscher FJ (August 1996). "KAP-1, a novel corepressor for the highly conserved KRAB repression domain". Genes Dev. 10 (16): 2067–78. doi:10.1101/gad.10.16.2067. PMID 8769649.
  5. Moosmann P, Georgiev O, Le Douarin B, Bourquin JP, Schaffner W (December 1996). "Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1". Nucleic Acids Res. 24 (24): 4859–67. doi:10.1093/nar/24.24.4859. PMC 146346. PMID 9016654.
  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. doi:10.1101/gr.275607.121. ISSN 1549-5469. PMC 8559706. PMID 34407984.
  7. Basel Institute for Immunology (1988). Annual Report. Basel. p. 53. ISSN 0301-3782. OCLC 1793356.{{cite book}}: CS1 maint: location missing publisher (link)
  8. Thiesen HJ (April 1990). "Multiple genes encoding zinc finger domains are expressed in human T cells" (PDF). New Biol. 2 (4): 363–74. PMID 2288909.
  9. Bellefroid EJ, Poncelet DA, Lecocq PJ, Revelant O, Martial JA (May 1991). "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. Bibcode:1991PNAS...88.3608B. doi:10.1073/pnas.88.9.3608. PMC 51501. PMID 2023909.
  10. Thiesen HJ, Bellefroid E, Revelant O, Martial JA (July 1991). "Conserved KRAB protein domain identified upstream from the zinc finger region of Kox 8". Nucleic Acids Res. 19 (14): 3996. doi:10.1093/nar/19.14.3996. PMC 328495. PMID 1861988.
  11. Rousseau-Merck MF, Koczan D, Legrand I, Möller S, Autran S, Thiesen HJ (2002). "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. doi:10.1159/000069802. PMID 12697996. S2CID 29964545.

Further reading


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