UniProt functional annotation for P48552



	UniProt functional annotation for P48552

UniProt code: P48552.

Organism: Homo sapiens (Human).

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

Function: Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors. Positive regulator of the circadian clock gene expression: stimulates transcription of ARNTL/BMAL1, CLOCK and CRY1 by acting as a coactivator for RORA and RORC. Involved in the regulation of ovarian function (By similarity). Plays a role in renal development (PubMed:28381549). {ECO:0000250|UniProtKB:Q8CBD1, ECO:0000269|PubMed:10364267, ECO:0000269|PubMed:11509661, ECO:0000269|PubMed:11518808, ECO:0000269|PubMed:12554755, ECO:0000269|PubMed:15060175, ECO:0000269|PubMed:21628546, ECO:0000269|PubMed:28381549, ECO:0000269|PubMed:7641693}.

Subunit: Interacts with RARA and RXRB homodimers and RARA/RXRB heterodimers in the presence of ligand. Interacts with HDAC1 and HDAC3 via its N-terminal domain. Interacts with NR2C1 (sumoylated form and via the ligand-binding domain); the interaction results in promoting the repressor activity of NR2C1 (By similarity). Interacts with CTBP1, CTBP2, ESR1, HDAC1, HDAC2, HDAC5, HDAC6, NR2C2, NR3C1, NR3C2, YWHAH, JUN and FOS. Found in a complex with both NR3C1 and YWHAH. Interacts with ZNF366. Interacts with RORA. {ECO:0000250|UniProtKB:Q8CBD1, ECO:0000269|PubMed:10364267, ECO:0000269|PubMed:11266503, ECO:0000269|PubMed:11509661, ECO:0000269|PubMed:11518808, ECO:0000269|PubMed:12554755, ECO:0000269|PubMed:12773562, ECO:0000269|PubMed:14736873, ECO:0000269|PubMed:15060175, ECO:0000269|PubMed:16887930, ECO:0000269|PubMed:16990259, ECO:0000269|PubMed:17085477, ECO:0000269|PubMed:21628546, ECO:0000269|PubMed:7641693, ECO:0000269|PubMed:9556573}.

Subcellular location: Nucleus {ECO:0000269|PubMed:11266503, ECO:0000269|PubMed:12773562, ECO:0000269|PubMed:15060175, ECO:0000269|PubMed:7641693}. Note=Localized to discrete foci and redistributes to larger nuclear domains upon binding to ligand-bound NR3C1.

Induction: Expressed in a circadian manner in the liver (at protein level). {ECO:0000269|PubMed:21628546}.

Domain: Contains 9 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, which have different affinities for nuclear receptors. The C-terminal LTKTNPILYYMLQK motif is required for ligand-dependent interaction with RAAR and RXRB homodimers and heterodimers, for the corepressor activity, and for the formation of an HDAC3 complex with RARA/RXRB (By similarity). Contains at least four autonomous repression domains (RD1- 4). RD1 functions via a histone deacetylase (HDAC)-independent mechanism, whereas RD2, RD3 and RD4 can function by HDAC-dependent or independent mechanisms, depending on cell type. RD2 is dependent on CTBP binding. {ECO:0000250}.

Ptm: Acetylation regulates its nuclear translocation and corepressive activity (By similarity). Acetylation abolishes interaction with CTBP1. Phosphorylation enhances interaction with YWHAH. {ECO:0000250, ECO:0000269|PubMed:11509661}.

Disease: Congenital anomalies of kidney and urinary tract 3 (CAKUT3) [MIM:618270]: A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children. CAKUT3 inheritance is autosomal dominant. {ECO:0000269|PubMed:28381549, ECO:0000269|PubMed:30143558}. Note=The disease is caused by variants affecting the gene represented in this entry.

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:		Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors. Positive regulator of the circadian clock gene expression: stimulates transcription of ARNTL/BMAL1, CLOCK and CRY1 by acting as a coactivator for RORA and RORC. Involved in the regulation of ovarian function (By similarity). Plays a role in renal development (PubMed:28381549). {ECO:0000250\|UniProtKB:Q8CBD1, ECO:0000269\|PubMed:10364267, ECO:0000269\|PubMed:11509661, ECO:0000269\|PubMed:11518808, ECO:0000269\|PubMed:12554755, ECO:0000269\|PubMed:15060175, ECO:0000269\|PubMed:21628546, ECO:0000269\|PubMed:28381549, ECO:0000269\|PubMed:7641693}.


Subunit:		Interacts with RARA and RXRB homodimers and RARA/RXRB heterodimers in the presence of ligand. Interacts with HDAC1 and HDAC3 via its N-terminal domain. Interacts with NR2C1 (sumoylated form and via the ligand-binding domain); the interaction results in promoting the repressor activity of NR2C1 (By similarity). Interacts with CTBP1, CTBP2, ESR1, HDAC1, HDAC2, HDAC5, HDAC6, NR2C2, NR3C1, NR3C2, YWHAH, JUN and FOS. Found in a complex with both NR3C1 and YWHAH. Interacts with ZNF366. Interacts with RORA. {ECO:0000250\|UniProtKB:Q8CBD1, ECO:0000269\|PubMed:10364267, ECO:0000269\|PubMed:11266503, ECO:0000269\|PubMed:11509661, ECO:0000269\|PubMed:11518808, ECO:0000269\|PubMed:12554755, ECO:0000269\|PubMed:12773562, ECO:0000269\|PubMed:14736873, ECO:0000269\|PubMed:15060175, ECO:0000269\|PubMed:16887930, ECO:0000269\|PubMed:16990259, ECO:0000269\|PubMed:17085477, ECO:0000269\|PubMed:21628546, ECO:0000269\|PubMed:7641693, ECO:0000269\|PubMed:9556573}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:11266503, ECO:0000269\|PubMed:12773562, ECO:0000269\|PubMed:15060175, ECO:0000269\|PubMed:7641693}. Note=Localized to discrete foci and redistributes to larger nuclear domains upon binding to ligand-bound NR3C1.
Induction:		Expressed in a circadian manner in the liver (at protein level). {ECO:0000269\|PubMed:21628546}.
Domain:		Contains 9 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, which have different affinities for nuclear receptors. The C-terminal LTKTNPILYYMLQK motif is required for ligand-dependent interaction with RAAR and RXRB homodimers and heterodimers, for the corepressor activity, and for the formation of an HDAC3 complex with RARA/RXRB (By similarity). Contains at least four autonomous repression domains (RD1- 4). RD1 functions via a histone deacetylase (HDAC)-independent mechanism, whereas RD2, RD3 and RD4 can function by HDAC-dependent or independent mechanisms, depending on cell type. RD2 is dependent on CTBP binding. {ECO:0000250}.
Ptm:		Acetylation regulates its nuclear translocation and corepressive activity (By similarity). Acetylation abolishes interaction with CTBP1. Phosphorylation enhances interaction with YWHAH. {ECO:0000250, ECO:0000269\|PubMed:11509661}.
Disease:		Congenital anomalies of kidney and urinary tract 3 (CAKUT3) [MIM:618270]: A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children. CAKUT3 inheritance is autosomal dominant. {ECO:0000269\|PubMed:28381549, ECO:0000269\|PubMed:30143558}. Note=The disease is caused by variants affecting the gene represented in this entry.