| Structural highlights
Function
[TIF1B_HUMAN] Nuclear corepressor for KRAB domain-containing zinc finger proteins (KRAB-ZFPs). Mediates gene silencing by recruiting CHD3, a subunit of the nucleosome remodeling and deacetylation (NuRD) complex, and SETDB1 (which specifically methylates histone H3 at 'Lys-9' (H3K9me)) to the promoter regions of KRAB target genes. Enhances transcriptional repression by coordinating the increase in H3K9me, the decrease in histone H3 'Lys-9 and 'Lys-14' acetylation (H3K9ac and H3K14ac, respectively) and the disposition of HP1 proteins to silence gene expression. Recruitment of SETDB1 induces heterochromatinization. May play a role as a coactivator for CEBPB and NR3C1 in the transcriptional activation of ORM1. Also corepressor for ERBB4. Inhibits E2F1 activity by stimulating E2F1-HDAC1 complex formation and inhibiting E2F1 acetylation. May serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of RB1. Important regulator of CDKN1A/p21(CIP1). Has E3 SUMO-protein ligase activity toward itself via its PHD-type zinc finger. Also specifically sumoylates IRF7, thereby inhibiting its transactivation activity. Ubiquitinates p53/TP53 leading to its proteosomal degradation; the function is enhanced by MAGEC2 and MAGEA2, and possibly MAGEA3 and MAGEA6.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, alpha(Z), of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.
Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing.,Zeng L, Yap KL, Ivanov AV, Wang X, Mujtaba S, Plotnikova O, Rauscher FJ 3rd, Zhou MM Nat Struct Mol Biol. 2008 Jun;15(6):626-33. Epub 2008 May 18. PMID:18488044[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Friedman JR, Fredericks WJ, Jensen DE, Speicher DW, Huang XP, Neilson EG, Rauscher FJ 3rd. KAP-1, a novel corepressor for the highly conserved KRAB repression domain. Genes Dev. 1996 Aug 15;10(16):2067-78. PMID:8769649
- ↑ 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. 1996 Dec 15;24(24):4859-67. PMID:9016654
- ↑ Agata Y, Matsuda E, Shimizu A. Two novel Kruppel-associated box-containing zinc-finger proteins, KRAZ1 and KRAZ2, repress transcription through functional interaction with the corepressor KAP-1 (TIF1beta/KRIP-1). J Biol Chem. 1999 Jun 4;274(23):16412-22. PMID:10347202
- ↑ Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 2002 Apr 15;16(8):919-32. PMID:11959841 doi:http://dx.doi.org/10.1101/gad.973302
- ↑ Lechner MS, Schultz DC, Negorev D, Maul GG, Rauscher FJ 3rd. The mammalian heterochromatin protein 1 binds diverse nuclear proteins through a common motif that targets the chromoshadow domain. Biochem Biophys Res Commun. 2005 Jun 17;331(4):929-37. PMID:15882967 doi:http://dx.doi.org/10.1016/j.bbrc.2005.04.016
- ↑ Wang C, Ivanov A, Chen L, Fredericks WJ, Seto E, Rauscher FJ 3rd, Chen J. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 2005 Sep 21;24(18):3279-90. Epub 2005 Aug 18. PMID:16107876 doi:http://dx.doi.org/10.1038/sj.emboj.7600791
- ↑ White DE, Negorev D, Peng H, Ivanov AV, Maul GG, Rauscher FJ 3rd. KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions. Cancer Res. 2006 Dec 15;66(24):11594-9. PMID:17178852 doi:http://dx.doi.org/10.1158/0008-5472.CAN-06-4138
- ↑ Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC, Lukas J, Bekker-Jensen S, Bartek J, Shiloh Y. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol. 2006 Aug;8(8):870-6. Epub 2006 Jul 23. PMID:16862143 doi:http://dx.doi.org/10.1038/ncb1446
- ↑ Lee YK, Thomas SN, Yang AJ, Ann DK. Doxorubicin down-regulates Kruppel-associated box domain-associated protein 1 sumoylation that relieves its transcription repression on p21WAF1/CIP1 in breast cancer MCF-7 cells. J Biol Chem. 2007 Jan 19;282(3):1595-606. Epub 2006 Nov 1. PMID:17079232 doi:http://dx.doi.org/10.1074/jbc.M606306200
- ↑ Wang C, Rauscher FJ 3rd, Cress WD, Chen J. Regulation of E2F1 function by the nuclear corepressor KAP1. J Biol Chem. 2007 Oct 12;282(41):29902-9. Epub 2007 Aug 17. PMID:17704056 doi:10.1074/jbc.M704757200
- ↑ Li X, Lee YK, Jeng JC, Yen Y, Schultz DC, Shih HM, Ann DK. Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. J Biol Chem. 2007 Dec 14;282(50):36177-89. Epub 2007 Oct 17. PMID:17942393 doi:http://dx.doi.org/10.1074/jbc.M706912200
- ↑ Ivanov AV, Peng H, Yurchenko V, Yap KL, Negorev DG, Schultz DC, Psulkowski E, Fredericks WJ, White DE, Maul GG, Sadofsky MJ, Zhou MM, Rauscher FJ 3rd. PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol Cell. 2007 Dec 14;28(5):823-37. PMID:18082607 doi:http://dx.doi.org/10.1016/j.molcel.2007.11.012
- ↑ Suzuki C, Murakumo Y, Kawase Y, Sato T, Morinaga T, Fukuda N, Enomoto A, Ichihara M, Takahashi M. A novel GDNF-inducible gene, BMZF3, encodes a transcriptional repressor associated with KAP-1. Biochem Biophys Res Commun. 2008 Feb 1;366(1):226-32. Epub 2007 Dec 3. PMID:18060868 doi:http://dx.doi.org/S0006-291X(07)02541-7
- ↑ Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub , 2010 Sep 21. PMID:20858735 doi:10.1158/1541-7786.MCR-10-0042
- ↑ Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell. 2010 Sep 24;39(6):963-74. PMID:20864041 doi:10.1016/j.molcel.2010.08.029
- ↑ Li X, Lin HH, Chen H, Xu X, Shih HM, Ann DK. SUMOylation of the transcriptional co-repressor KAP1 is regulated by the serine and threonine phosphatase PP1. Sci Signal. 2010 Apr 27;3(119):ra32. doi: 10.1126/scisignal.2000781. PMID:20424263 doi:http://dx.doi.org/10.1126/scisignal.2000781
- ↑ Liang Q, Deng H, Li X, Wu X, Tang Q, Chang TH, Peng H, Rauscher FJ 3rd, Ozato K, Zhu F. Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. J Immunol. 2011 Nov 1;187(9):4754-63. doi: 10.4049/jimmunol.1101704. Epub 2011, Sep 21. PMID:21940674 doi:http://dx.doi.org/10.4049/jimmunol.1101704
- ↑ Zeng L, Yap KL, Ivanov AV, Wang X, Mujtaba S, Plotnikova O, Rauscher FJ 3rd, Zhou MM. Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing. Nat Struct Mol Biol. 2008 Jun;15(6):626-33. Epub 2008 May 18. PMID:18488044 doi:10.1038/nsmb.1416
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