ArticleBiochemistry2015
Biochemical and structural characterization of HDAC8 mutants associated with Cornelia de Lange syndrome spectrum disorders.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- Reversible acetylation of HDAC8 regulates cell cycle.EMBO reports · 2024Article
- Intrinsic structural dynamics dictate enzymatic activity and inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Cryo-EM structure of the Saccharomyces cerevisiae Rpd3L histone deacetylase complex.Nature communications · 2023Article
- HDAC8 Deacetylates HIF-1α and Enhances Its Protein Stability to Promote Tumor Growth and Migration in Melanoma.Cancers · 2023Article
- Phage-assisted, active site-directed ligand evolution of a potent and selective histone deacetylase 8 inhibitor.Protein science : a publication of the Protein Society · 2022Article
- Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors.International journal of molecular sciences · 2022Article
- A Novel Intragenic Duplication in theGenes · 2022Article
- A novel de novo HDAC8 missense mutation causing Cornelia de Lange syndrome.Molecular genetics & genomic medicine · 2021Article
- Aromatic side-chain flips orchestrate the conformational sampling of functional loops in human histone deacetylase 8.Chemical science · 2021Article
- Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders.Journal of structural biology · 2021Article
- Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine.Epigenetics insights · 2021Article
- An in silico mechanistic insight into HDAC8 activation facilitates the discovery of new small-molecule activators.Bioorganic & medicinal chemistry · 2020Article
- Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases.Current opinion in structural biology · 2019Review
- Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth HalophileBiochemistry · 2019Article
- Preparation of a new construct of human histone deacetylase 8 for the crystallization of enzyme-inhibitor complexes.Methods in enzymology · 2019Article
- The enzyme activity of histone deacetylase 8 is modulated by a redox-switch.Redox biology · 2019Article
- The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines.Archives of toxicology · 2018Article
- Histone deacetylase 8 protects human proximal tubular epithelial cells from hypoxia-mimetic cobalt- and hypoxia/reoxygenation-induced mitochondrial fission and cytotoxicity.Scientific reports · 2018Article
- HDAC8 Substrates Identified by Genetically Encoded Active Site Photocrosslinking.Journal of the American Chemical Society · 2017Article
- Analysis of the interactome of Schistosoma mansoni histone deacetylase 8.PLoS neglected tropical diseases · 2017Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Cornelia de Lange Syndrome (CdLS) spectrum disorders are characterized by multiple organ system congenital anomalies that result from mutations in genes encoding core cohesin proteins SMC1A, SMC3, and RAD21, or proteins that regulate cohesin function such as NIPBL and HDAC8. HDAC8 is the Zn(2+)-dependent SMC3 deacetylase required for cohesin recycling during the cell cycle, and 17 different HDAC8 mutants have been identified to date in children diagnosed with CdLS. As part of our continuing studies focusing on aberrant HDAC8 function in CdLS, we now report the preparation and biophysical evaluation of five human HDAC8 mutants: P91L, G117E, H180R, D233G, and G304R. Additionally, the double mutants D233G-Y306F and P91L-Y306F were prepared to enable cocrystallization of intact enzyme-substrate complexes. X-ray crystal structures of G117E, P91L-Y306F, and D233G-Y306F HDAC8 mutants reveal that each CdLS mutation causes structural changes that compromise catalysis and/or thermostability. For example, the D233G mutation disrupts the D233-K202-S276 hydrogen bond network, which stabilizes key tertiary structure interactions, thereby significantly compromising thermostability. Molecular dynamics simulations of H180R and G304R HDAC8 mutants suggest that the bulky arginine side chain of each mutant protrudes into the substrate binding site and also causes active site residue Y306 to fluctuate away from the position required for substrate activation and catalysis. Significantly, the catalytic activities of most mutants can be partially or fully rescued by the activator N-(phenylcarbamothioyl)-benzamide, suggesting that HDAC8 activators may serve as possible leads in the therapeutic management of CdLS.
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