UniProt functional annotation for P56524



	UniProt functional annotation for P56524

UniProt code: P56524.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256). {ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:24413532, ECO:0000269|PubMed:27708256}.

Catalytic activity: Reaction=H2O + N(6)-acetyl-L-lysyl-[histone] = acetate + L-lysyl- [histone]; Xref=Rhea:RHEA:58196, Rhea:RHEA-COMP:9845, Rhea:RHEA- COMP:11338, ChEBI:CHEBI:15377, ChEBI:CHEBI:29969, ChEBI:CHEBI:30089, ChEBI:CHEBI:61930; EC=3.5.1.98;

Subunit: Homodimer. Homodimerization via its N-terminal domain (PubMed:12032081). Interacts with MEF2A (PubMed:10487761). Interacts with MEF2C and MEF2D (PubMed:10523670). Interacts with AHRR (By similarity). Interacts with NR2C1 (PubMed:11463856). Interacts with HDAC7 (By similarity). Interacts with a 14-3-3 chaperone protein in a phosphorylation dependent manner (PubMed:10958686). Interacts with BTBD14B (By similarity). Interacts with KDM5B (PubMed:17373667). Interacts with MYOCD (By similarity). Interacts with MORC2 (PubMed:20110259). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2 (PubMed:25752541). Interacts with EP300 in the presence of TFAP2C (PubMed:24413532). Interacts with HSPA1A and HSPA1B leading to their deacetylation at 'Lys-77' (PubMed:27708256). Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with DHX36 (By similarity). Interacts with SIK3; this interaction leads to HDAC4 retention in the cytoplasm (By similarity). Interacts with ZNF638 (PubMed:30487602). {ECO:0000250|UniProtKB:Q6NZM9, ECO:0000250|UniProtKB:Q99P99, ECO:0000269|PubMed:10487761, ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:10958686, ECO:0000269|PubMed:11463856, ECO:0000269|PubMed:17373667, ECO:0000269|PubMed:20110259, ECO:0000269|PubMed:22649097, ECO:0000269|PubMed:24413532, ECO:0000269|PubMed:25752541, ECO:0000269|PubMed:27708256, ECO:0000269|PubMed:30487602}.

Subcellular location: Nucleus. Cytoplasm. Note=Shuttles between the nucleus and the cytoplasm. Upon muscle cells differentiation, it accumulates in the nuclei of myotubes, suggesting a positive role of nuclear HDAC4 in muscle differentiation. The export to cytoplasm depends on the interaction with a 14-3-3 chaperone protein and is due to its phosphorylation at Ser-246, Ser-467 and Ser-632 by CaMK4 and SIK1. The nuclear localization probably depends on sumoylation. Interaction with SIK3 leads to HDAC4 retention in the cytoplasm (By similarity). {ECO:0000250|UniProtKB:Q6NZM9}.

Tissue specificity: Ubiquitous.

Domain: The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.

Domain: The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2. {ECO:0000269|PubMed:22649097}.

Ptm: Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-350, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high- affinity docking site for 14-3-3. {ECO:0000269|PubMed:10958686, ECO:0000269|PubMed:22649097}.

Ptm: Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4. {ECO:0000269|PubMed:12032081}.

Disease: 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. {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, ECO:0000269|PubMed:24715439}. Note=The gene represented in this entry is involved in disease pathogenesis. HDAC4 point mutations and chromosomal microdeletions encompassing this gene have been found in BDMR patients (PubMed:20691407, PubMed:24715439, PubMed:23188045). However, HDAC4 haploinsufficiency is not fully penetrant and multiple genes may contribute to manifestation of the full phenotypic spectrum (PubMed:24715439, PubMed:23188045). {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, ECO:0000269|PubMed:24715439}.

Similarity: Belongs to the histone deacetylase family. HD type 2 subfamily. {ECO:0000305}.

Sequence caution: Sequence=BAA22957.2; Type=Erroneous initiation; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256). {ECO:0000269\|PubMed:10523670, ECO:0000269\|PubMed:24413532, ECO:0000269\|PubMed:27708256}.


Catalytic activity:		Reaction=H2O + N(6)-acetyl-L-lysyl-[histone] = acetate + L-lysyl- [histone]; Xref=Rhea:RHEA:58196, Rhea:RHEA-COMP:9845, Rhea:RHEA- COMP:11338, ChEBI:CHEBI:15377, ChEBI:CHEBI:29969, ChEBI:CHEBI:30089, ChEBI:CHEBI:61930; EC=3.5.1.98;
Subunit:		Homodimer. Homodimerization via its N-terminal domain (PubMed:12032081). Interacts with MEF2A (PubMed:10487761). Interacts with MEF2C and MEF2D (PubMed:10523670). Interacts with AHRR (By similarity). Interacts with NR2C1 (PubMed:11463856). Interacts with HDAC7 (By similarity). Interacts with a 14-3-3 chaperone protein in a phosphorylation dependent manner (PubMed:10958686). Interacts with BTBD14B (By similarity). Interacts with KDM5B (PubMed:17373667). Interacts with MYOCD (By similarity). Interacts with MORC2 (PubMed:20110259). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2 (PubMed:25752541). Interacts with EP300 in the presence of TFAP2C (PubMed:24413532). Interacts with HSPA1A and HSPA1B leading to their deacetylation at 'Lys-77' (PubMed:27708256). Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with DHX36 (By similarity). Interacts with SIK3; this interaction leads to HDAC4 retention in the cytoplasm (By similarity). Interacts with ZNF638 (PubMed:30487602). {ECO:0000250\|UniProtKB:Q6NZM9, ECO:0000250\|UniProtKB:Q99P99, ECO:0000269\|PubMed:10487761, ECO:0000269\|PubMed:10523670, ECO:0000269\|PubMed:10958686, ECO:0000269\|PubMed:11463856, ECO:0000269\|PubMed:17373667, ECO:0000269\|PubMed:20110259, ECO:0000269\|PubMed:22649097, ECO:0000269\|PubMed:24413532, ECO:0000269\|PubMed:25752541, ECO:0000269\|PubMed:27708256, ECO:0000269\|PubMed:30487602}.
Subcellular location:		Nucleus. Cytoplasm. Note=Shuttles between the nucleus and the cytoplasm. Upon muscle cells differentiation, it accumulates in the nuclei of myotubes, suggesting a positive role of nuclear HDAC4 in muscle differentiation. The export to cytoplasm depends on the interaction with a 14-3-3 chaperone protein and is due to its phosphorylation at Ser-246, Ser-467 and Ser-632 by CaMK4 and SIK1. The nuclear localization probably depends on sumoylation. Interaction with SIK3 leads to HDAC4 retention in the cytoplasm (By similarity). {ECO:0000250\|UniProtKB:Q6NZM9}.
Tissue specificity:		Ubiquitous.
Domain:		The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.
Domain:		The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2. {ECO:0000269\|PubMed:22649097}.
Ptm:		Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-350, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high- affinity docking site for 14-3-3. {ECO:0000269\|PubMed:10958686, ECO:0000269\|PubMed:22649097}.
Ptm:		Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4. {ECO:0000269\|PubMed:12032081}.
Disease:		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. {ECO:0000269\|PubMed:20691407, ECO:0000269\|PubMed:23188045, ECO:0000269\|PubMed:24715439}. Note=The gene represented in this entry is involved in disease pathogenesis. HDAC4 point mutations and chromosomal microdeletions encompassing this gene have been found in BDMR patients (PubMed:20691407, PubMed:24715439, PubMed:23188045). However, HDAC4 haploinsufficiency is not fully penetrant and multiple genes may contribute to manifestation of the full phenotypic spectrum (PubMed:24715439, PubMed:23188045). {ECO:0000269\|PubMed:20691407, ECO:0000269\|PubMed:23188045, ECO:0000269\|PubMed:24715439}.
Similarity:		Belongs to the histone deacetylase family. HD type 2 subfamily. {ECO:0000305}.
Sequence caution:		Sequence=BAA22957.2; Type=Erroneous initiation; Evidence={ECO:0000305};