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HDAC8

ENST00000373573 | p.His201Tyr

predicted deleterious | pathogenicity score: 97%

» Summary
» Literature
» Helix prediction details
» Evolutionary pressure
» Structure

Summary

HDAC8 - ENST00000373573

Gene

HDAC8 - ENSG00000147099 | ENSP00000362674 | ENST00000373573
Ensembl | RefSeq | UniProt

Location

GRCh38 X:72329516-72573199 Ensembl UCSC

Description

histone deacetylase 8

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. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. {ECO:0000269|PubMed:10748112, ECO:0000269|PubMed:10922473, ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:22885700}.;

Condition(s)

Cornelia de Lange syndrome 5 (CDLS5)

A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies.
The disease is caused by mutations affecting the gene represented in this entry. OMIM
Wilson-Turner X-linked mental retardation syndrome (WTS)

A neurologic disorder characterized by severe intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Affected females have a milder phenotype than affected males.
The disease is caused by mutations affecting the gene represented in this entry. OMIM

Sequence

PDB and PDB position

3f07 201 (Explore)

gnomAD

This variant is not present in gnomAD .

Pathogenicity

97%

Agreement:

Data quality:

Older predictions

Literature

Literature for structurally equivalent variants in homologous proteins

The following papers were found describing variants in proteins homologous to HDAC8.
Structurally, these variants are located at an equivalent position compared to .

First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.

Alterations in the chromatin structure are preferentially involved in the regulation of cell functions, including gene expression, in eukaryotes. Three types of mechanisms, by which the alterations are caused have been reported: (i) variants of histone subtypes, (ii) chromatin remodeling, and (iii) post-translational modification. This review focuses mainly on the first and third mechanisms, especially on the acetylation of core histones, one of the third mechanisms. Using the gene targeting technique for the DT40 chicken B cell line, we systematically generated a number of mutants, respectively, devoid of particular genes encoding histones and histone deacetylase(s) (HDACs). Most of the H1 and core histone variants should be involved positively or negatively in the transcription regulation of particular genes. Of the chicken HDACs (chHDACs), chHDAC-2 controls the amount of the IgM H-chain at the steps of both transcription and alternative pre-mRNA processing, and chHDAC-3 is essential for cell viability, whereas chHDAC-1 merely affects gene expression in DT40 cells. These results indicate that HDAC family members should participate, in combination with one another, and/or histone acetyltransferase(s) (HATs), in the acetylation of core histones that regulates gene expression through alterations in the chromatin structure.

p53, the most commonly mutated gene in cancer cells, directs cell cycle arrest or induces programmed cell death (apoptosis) in response to stress. It has been demonstrated that p53 activity is up-regulated in part by posttranslational acetylation. In agreement with these observations, here we show that mammalian histone deacetylase (HDAC)-1, -2, and -3 are all capable of down-regulating p53 function. Down-regulation of p53 activity by HDACs is HDAC dosage-dependent, requires the deacetylase activity of HDACs, and depends on the region of p53 that is acetylated by p300/CREB-binding protein (CBP). These results suggest that interactions of p53 and HDACs likely result in p53 deacetylation, thereby reducing its transcriptional activity. In support of this idea, GST pull-down and immunoprecipitation assays show that p53 interacts with HDAC1 both in vitro and in vivo. Furthermore, a pre-acetylated p53 peptide was significantly deacetylated by immunoprecipitated wild type HDAC1 but not deacetylase mutant. Also, co-expression of HDAC1 greatly reduced the in vivo acetylation level of p53. Finally, we report that the activation potential of p53 on the BAX promoter, a natural p53-responsive system, is reduced in the presence of HDACs. Taken together, our findings indicate that deacetylation of p53 by histone deacetylases is likely to be part of the mechanisms that control the physiological activity of p53.

Histone deacetylases (HDACs) are involved in the deacetylation of core histones, which is related to transcription regulation in eukaryotes through alterations in the chromatin structure. We cloned cDNA and genomic DNA encoding a chicken HDAC, chHDAC-3, which was localized in both the nuclei and cytoplasm in DT40 cells. Although one of the two chHDAC-3 alleles could be disrupted with high efficiency, no homozygous mutants were obtained after a second round of the gene-targeting technique due to its necessity for DT40 cells. We introduced a chHDAC-3 transgene under the control of a tetracycline-responsive promoter into the heterozygous mutant and subsequently disrupted the remaining endogenous chHDAC-3 allele to generate the homozygous chHDAC-3-deficient mutant, DeltachHDAC-3/FHDAC3. Inhibition of the expression of the regulatable chHDAC-3 transgene caused apoptotic cell death of the mutant. Complementation experiments involving truncated and missense chHDAC-3 mutant proteins revealed that the 1-23 N-terminal sequence, the 389-417 C-terminal sequence, the nuclear export signal, and the deacetylation activity of chHDAC-3 were essential for the cell viability. Taken together, these results indicate that chHDAC-3 plays an essential role, probably as a scavenger in the cytoplasm, in the proliferation of DT40 cells.

The Drosophila gene groucho (gro) encodes a transcriptional corepressor that has critical roles in many development processes. In an effort to illuminate the mechanism of Gro-mediated repression, we have employed Gro as an affinity reagent to purify Gro-binding proteins from embryonic nuclear extracts. One of these proteins was found to be the histone deacetylase Rpd3. Protein-protein interaction assays suggest that Gro and Rpd3 form a complex in vivo and that they interact directly via the glycine/proline rich (GP) domain in Gro. Cell culture assays demonstrate that Rpd3 potentiates repression by the GP domain. Furthermore, experiments employing a histone deacetylase inhibitor, as well as a catalytically inactive form of Rpd3, imply that histone deacetylase activity is required for efficient Gro-mediated repression. Finally, mutations in gro and rpd3 have synergistic effects on embryonic lethality and pattern formation. These findings support the view that Gro mediates repression, at least in part, by the direct recruitment of the histone deacetylase Rpd3 to the template, where it can modulate local chromatin structure. They also provide evidence for a specific role of Rpd3 in early development.

The function of eukaryotic histone deacetylase (HDAC) has been extensively studied for its critical role in transcriptional regulation and carcinogenesis. However that of the prokaryotic counterpart remains largely unknown. Recently, we cloned HDAC-like protein in Thermus caldophilus GK24 (Tca HDAC) from a genomic library of the microorganism based on homology analysis with human HDAC1. To explore the function of Tca HDAC in mammalian cells, Tca HDAC gene expressing vector was transfected into a human fibrosarcoma cell line, HT1080. Tca HDAC was mainly localized in nuclei of the mammalian cells as a human HDAC1 was, due to an N-terminal HDAC association domain. We further generated histidine-substituted Tca HDAC mutants and investigated their role in biochemical and cellular activity of the enzyme. Tca HDAC mutants exhibited dramatic loss of enzymatic activity and conditioned media (CM) from HT1080 cells transfected with mutant Tca HDAC was unable to stimulate angiogenic phenotypes of endothelial cells in vitro whereas that of wild Tca HDAC did. Collectively, these results demonstrate that a prokaryotic histone deacetylase from T. caldophilus GK24 is functionally active in mammalian cells and its function in gene expression is conserved from prokaryotes to eukaryotes.

The silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) mediates transcriptional repression by recruiting histone deacetylases (HDACs) to the DNA-bound nuclear receptor complex. The full-length SMRT (SMRTe) contains an N-terminal sequence that is highly conserved to the nuclear receptor corepressor N-CoR. To date, little is known about the activity and function of the full-length SMRTe protein, despite extensive studies on separated receptor interaction and transcriptional repression domains. Here we show that SMRTe inhibits MEF2C transcriptional activation by targeting selective HDACs to unique subnuclear domains. Indirect immunofluorescence studies with anti-SMRTe antibody reveal discrete cytoplasmic and nuclear speckles, which contain RARalpha in an RA-sensitive manner. Formation of the SMRTe nuclear speckles results in recruitment of several class I and class II HDACs to these subnuclear domains in a process depending on HDAC enzymatic activity. Intriguingly, although HDAC4 is located primarily in the cytoplasm, coexpression of SMRTe dramatically translocates HDAC4 from the cytoplasm into the nucleus, where HDAC4 prevents MEF2C from activating muscle differentiation. SMRTe also translocates HDAC5 from diffusive nucleoplasm into discrete nuclear domains. Accordingly, SMRTe synergizes with HDAC4 and 5 to inhibit MEF2C transactivation of target promoter, suggesting that nuclear domain targeting of HDAC4/5 may be important in preventing muscle cell differentiation. These results highlight an unexpected new function of the nuclear receptor corepressor SMRTe for its role in regulating cellular trafficking of nuclear receptor and selective HDACs that may play an important role in regulation of cell growth and differentiation.

Treatment of mammalian cells with small molecule histone deacetylase (HDAC) inhibitors induces changes in the transcription of specific genes. These changes correlate directly with an increase in the acetylation levels of all four core histones in vivo. Antibodies directed against endogenous HDAC1, HDAC2, or HDAC3 immunoprecipitate histone deacetylase activity that is inhibited in vitro by the small molecule trapoxin (TPX), and all three HDACs are retained by a TPX-affinity matrix. HDAC1 and HDAC2 are associated in HeLa cells in a complex that is predominantly separate from an HDAC3 immune complex. Both Jurkat HDAC1 and HeLa HDAC1/2 immune complexes deacetylate all four core histones and recombinant HDAC1 deacetylates free and nucleosomal histones in vitro. Purified recombinant HDAC1 deacetylates core histones in the absence of protein cofactors. Site-directed mutagenesis was used to identify residues required for the enzymatic and structural integrity of HDAC1. Mutation of any one of four conserved residues causes deleterious effects on deacetylase activity and a reduced ability to bind a TPX-affinity matrix. A subset of these mutations also cause a decreased interaction with the HDAC1-associated proteins RbAp48 and mSin3A. Disruption of histone deacetylase activity either by TPX or by direct mutation of a histidine presumed to be in the active site abrogates HDAC1-mediated transcriptional repression of a targeted reporter gene in vivo.

Previous studies have shown that HDAC inhibitors selectively inhibit IL-2 gene expression, but the mechanism of this inhibition remains to be elucidated. It was recently reported that HDAC4, a component of the nuclear hormone receptor corepressor (N-CoR) complex, associates with the IL-2 promoter via the transcription factor myocyte enhancer factor 2 (MEF2). We therefore focused on the role of HDAC4/N-CoR complex in the transcriptional regulation of IL-2. Four approaches were used to characterize this role and to investigate the relation between the regulatory function of HDAC4/N-CoR complex and HDAC4-enzymatic activity: (i) HDAC4 silencing by RNA interference, (ii) overexpression of N-CoR repression domain 3 (RD3), (iii) overexpression of HDAC4 point mutants, and (iv) treatment with HDAC inhibitors. Here, we report that HDAC4 plays an essential role in IL-2 promoter activation, and that the formation of the HDAC4/N-CoR complex, which is closely related to HDAC4-enzymatic activity, might be involved in HDAC inhibitor-mediated inhibition of IL-2 gene expression. These observations indicate that the selective inhibition of HDAC4 or the interaction of HDAC4 with N-CoR is likely a potential target for the development of novel immunosuppressants.

The dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a type II C-type lectin whose expression is restricted to the most potent antigen-presenting cells (APCs), the dendritic cells (DCs). In recent years, DC-SIGN has gained an exponential increase in attention because of its involvement in multiple aspects of immune function. Besides being an adhesion molecule, particularly in binding ICAM-2 and ICAM-3, it is also crucial in recognizing several endogenous and exogenous antigens. Additionally, the intracellular domain of DC-SIGN includes molecular motifs, which enable the activation of signal transduction pathways involving Raf-1 and subsequent modulation of DC-maturation status, through direct modification of nuclear factor Nf-kappaB in DCs. Upon DC-SIGN engagement by mannose- or fucose-containing oligosaccharides, the latter leads to a tailored Toll-like receptor signalling, resulting in an altered DC-cytokine profile and skewing of Th1/Th2 responses. In this article, we will discuss recent advances on a broad perspective concerning DC-SIGN structure, signalling and immune function.

Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on standard substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nepsilon2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this "gain of function phenotype" could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro. Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.

Helix prediction details

Prediction: pathogenic 97%

The His201Tyr mutation in the protein has been classified as pathogenic by our ensemble classifier system, with very high confidence. There is a 98% agreement between all subclassifiers.

Data quality

Data quality for this region is considered good. This means that enhanced, deep alignments are present and there is a variety of data for the algorithm to predict from.

Assistant summary

This is an automatically generated assessment, it is not reviewed by humans and only has partial access to the information contained in the report. Generating this may take some time.

Evolutionary pressure

Conservation

The wildtype was observed in 91.39% of the 22169 sequences analyzed. The variant type was observed in < 1% of observed sequences.

Structure

Toggle interactions

This residue is involved in 1 CationPi interaction, 1 Contact interaction, 4 Hydrogen Bonds, 3 Hydrophobic interactions and 1 PiPi interaction.

Interaction statistics were calculated using advanced molecular optimization techniques and may not be visible in the plain PDB file. Please download the YASARA scene to explore the interactions in more detail.