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| | ==Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor SP1 fragment== | | ==Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor SP1 fragment== |
| - | <StructureSection load='5zoo' size='340' side='right' caption='[[5zoo]], [[Resolution|resolution]] 1.85Å' scene=''> | + | <StructureSection load='5zoo' size='340' side='right'caption='[[5zoo]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zoo]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZOO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZOO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zoo]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZOO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZOO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zoo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zoo OCA], [http://pdbe.org/5zoo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zoo RCSB], [http://www.ebi.ac.uk/pdbsum/5zoo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zoo ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5zoo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zoo OCA], [https://pdbe.org/5zoo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zoo RCSB], [https://www.ebi.ac.uk/pdbsum/5zoo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zoo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN]] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[http://omim.org/entry/600430 600430]]. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.<ref>PMID:20691407</ref> | + | [https://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[https://omim.org/entry/600430 600430]. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.<ref>PMID:20691407</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN]] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). 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. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.<ref>PMID:10523670</ref> | + | [https://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). 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. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.<ref>PMID:10523670</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5zoo" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5zoo" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone deacetylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hwang, H J]] | + | [[Category: Large Structures]] |
| - | [[Category: Kim, J S]] | + | [[Category: Hwang HJ]] |
| - | [[Category: Park, S Y]] | + | [[Category: Kim JS]] |
| - | [[Category: Hydrolase]] | + | [[Category: Park SY]] |
| - | [[Category: Protein-peptide complex]]
| + | |
| Structural highlights
Disease
HDAC4_HUMAN Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:600430. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.[1]
Function
HDAC4_HUMAN Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). 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. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.[2]
Publication Abstract from PubMed
Modification of chromatin and related transcription factors by histone deacetylases (HDACs) is one of the major strategies for controlling gene expression in eukaryotes. The HDAC domains of class IIa HDACs repress the respective target genes by interacting with the C-terminal region of the silencing mediator for retinoid and thyroid receptor (SMRT) repression domain 3 (SRD3c). However, latent catalytic activity suggests that their roles as deacetylases in gene regulation are unclear. Here, we found that two conserved GSI-containing motifs of SRD3c are critical for HDAC4 binding. Two SMRT peptides including these motifs commonly form a beta-hairpin structure in the cleft and block the catalytic entry site of HDAC4. They interact mainly with class IIa HDAC-specific residues of HDAC4 in a closed conformation. Structure-guided mutagenesis confirmed critical interactions between the SMRT peptides and HDAC4 and -5 as well as the contribution of the Arg1369 residue in the first motif for optimal binding to the two HDACs. These results indicate that SMRT binding does not activate the cryptic deacetylase activity of HDAC4 and explain how class IIa HDACs and the SMRT-HDAC3 complex are coordinated during gene regulation.
Structural basis of the specific interaction of SMRT corepressor with histone deacetylase 4.,Park SY, Kim GS, Hwang HJ, Nam TH, Park HS, Song J, Jang TH, Lee YC, Kim JS Nucleic Acids Res. 2018 Oct 13. pii: 5128926. doi: 10.1093/nar/gky926. PMID:30321390[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, McLeod DR, Zondag S, Toriello HV, Magenis RE, Elsea SH. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010 Aug 13;87(2):219-28. doi: 10.1016/j.ajhg.2010.07.011. PMID:20691407 doi:10.1016/j.ajhg.2010.07.011
- ↑ Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th'ng J, Han J, Yang XJ. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol. 1999 Nov;19(11):7816-27. PMID:10523670
- ↑ Park SY, Kim GS, Hwang HJ, Nam TH, Park HS, Song J, Jang TH, Lee YC, Kim JS. Structural basis of the specific interaction of SMRT corepressor with histone deacetylase 4. Nucleic Acids Res. 2018 Oct 13. pii: 5128926. doi: 10.1093/nar/gky926. PMID:30321390 doi:http://dx.doi.org/10.1093/nar/gky926
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