| Structural highlights
4a69 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Related: | 1r2b, 1xc5, 1kkq |
| Activity: | Histone deacetylase, with EC number 3.5.1.98 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[HDAC3_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803).[1] [2] [3] [NCOR2_HUMAN] Transcriptional corepressor of NR4A2/NURR1 and acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state (By similarity). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 5 have different affinities for different nuclear receptors.
Publication Abstract from PubMed
Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule--D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P(4))--acting as an 'intermolecular glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P(4), which may act as a regulator--potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.
Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.,Watson PJ, Fairall L, Santos GM, Schwabe JW Nature. 2012 Jan 9;481(7381):335-40. doi: 10.1038/nature10728. PMID:22230954[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pillai VB, Sundaresan NR, Samant SA, Wolfgeher D, Trivedi CM, Gupta MP. Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activity during hypertrophy of cardiomyocytes. Mol Cell Biol. 2011 Jun;31(11):2349-63. doi: 10.1128/MCB.01205-10. Epub 2011 Mar , 28. PMID:21444723 doi:http://dx.doi.org/10.1128/MCB.01205-10
- ↑ Hatzi K, Jiang Y, Huang C, Garrett-Bakelman F, Gearhart MD, Giannopoulou EG, Zumbo P, Kirouac K, Bhaskara S, Polo JM, Kormaksson M, MacKerell AD Jr, Xue F, Mason CE, Hiebert SW, Prive GG, Cerchietti L, Bardwell VJ, Elemento O, Melnick A. A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Rep. 2013 Aug 15;4(3):578-88. doi: 10.1016/j.celrep.2013.06.016. Epub 2013, Aug 1. PMID:23911289 doi:http://dx.doi.org/10.1016/j.celrep.2013.06.016
- ↑ Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3. J Biol Chem. 2014 Oct 31;289(44):30625-34. doi: 10.1074/jbc.M114.571984. Epub, 2014 Sep 4. PMID:25190803 doi:http://dx.doi.org/10.1074/jbc.M114.571984
- ↑ Watson PJ, Fairall L, Santos GM, Schwabe JW. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature. 2012 Jan 9;481(7381):335-40. doi: 10.1038/nature10728. PMID:22230954 doi:10.1038/nature10728
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