Androgen receptor - Homo sapiens (Human)

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Ontologies

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Reviewed, UniProtKB/Swiss-Prot P10275 (ANDR_HUMAN)

Last modified July 7, 2009. Version 159. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Protein names

Recommended name:
    Androgen receptor
Alternative name(s):
    Dihydrotestosterone receptor
    Nuclear receptor subfamily 3 group C member 4

Gene names

Name:	AR
Synonyms:	DHTR, NR3C4

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Sequence length	919 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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Function	Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3. Ref.31 Ref.41 Ref.46 Ref.48
Subunit structure	Binds DNA as a homodimer. Part of a ternary complex containing AR, EFCAB6/DJBP and PARK7. Interacts with HIPK3 and NR0B2 in the presence of androgen. The ligand binding domain interacts with MYST2/HBO1 in the presence of dihydrotestosterone. Interacts with EFCAB6/DJBP, PELP1, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1, ZNF318 and RREB1. Interacts with ZMIZ1/ZIMP10 and ZMIZ2/ZMIP7 which both enhance its transactivation activity. Interacts with SLC30A9 and RAD54L2/ARIP4 By similarity. Interacts via the ligand-binding domain with LXXLL and FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 and MAGEA11. The AR N-terminal poly-Gln region binds Ran resulting in enhancement of AR-mediated transactivation. Ran-binding decreases as the poly-Gln length increases. Interacts with HIP1 (via coiled coil domain).
Subcellular location	Nucleus. Ref.7
Tissue specificity	Isoform 2 is mainly expressed in heart and skeletal muscle. Ref.7
Domain	Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal steroid-binding domain. In the presence of bound steroid the ligand-binding domain interacts with the N-terminal modulating domain, and thereby activates AR transcription factor activity. Agonist binding is required for dimerization and binding to target DNA. The transcription factor activity of the complex formed by ligand-activated AR and DNA is modulated by interactions with coactivator and corepressor proteins. Interaction with RANBP9 is mediated by both the N-terminal domain and the DNA-binding domain. Interaction with EFCAB6/DJBP is mediated by the DNA-binding domain. Ref.46 Ref.40
Post-translational modification	Sumoylated on Lys-386 (major) and Lys-520. Ref.27 Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-534 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression. Ref.35
Polymorphism	The poly-Gln region of AR is highly polymorphic and the number of Gln varies in the population (from 17 to 26). A smaller size of the poly-Gln region may be associated with the development of prostate cancer. The poly-Gly region of AR is polymorphic and ranges from 24 to 31 Gly. A poly-Gly region shorter or equal to 23 may be associated with the development of androgenetic alopecia.
Involvement in disease	Defects in AR are the cause of androgen insensitivity syndrome (AIS) [MIM:300068]; previously known as testicular feminization syndrome (TFM). AIS is an X-linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. Ref.2 Ref.16 Ref.42 Ref.56 Ref.58 Ref.61 Ref.63 Ref.64 Ref.65 Ref.66 Ref.67 Ref.68 Ref.70 Ref.71 Ref.75 Ref.76 Ref.78 Ref.80 Ref.82 Ref.84 Ref.85 Ref.87 Ref.96 Ref.97 Ref.98 Ref.100 Ref.101 Ref.102 Ref.103 Ref.104 Ref.105 Ref.107 Ref.108 Ref.110 Ref.111 Ref.112 Ref.118 Ref.120 Ref.121 Ref.124 Ref.125 Ref.127 Ref.128 Ref.129 Ref.130 Ref.133 Ref.136 Ref.137 Ref.138 Ref.141 Ref.143 Ref.144 Ref.145 Ref.146 Ref.147 Ref.148 Ref.149 Ref.150 Ref.151 Ref.153 Ref.156 Ref.157 Ref.162 Ref.163 Ref.164 Ref.165 Ref.169 Ref.172 Ref.173 Ref.176 Ref.177 Ref.179 Ref.182 Defects in AR are the cause of spinal and bulbar muscular atrophy X-linked type 1 (SMAX1) [MIM:313200]; also known as Kennedy disease. SMAX1 is an X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. SMAX1 is caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. Ref.181 Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. Defects in AR are the cause of androgen insensitivity syndrome partial (PAIS) [MIM:312300]; also known as Reifenstein syndrome. PAIS is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations.
Miscellaneous	In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity. The hormone-receptor complex appears to recognize discrete DNA sequences upstream of transcriptional start sites. Transcriptional activity is enhanced by binding to RANBP9. The level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome in response to hormone-ablation therapy. Inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer.
Sequence similarities	Belongs to the nuclear hormone receptor family. NR3 subfamily. Contains 1 nuclear receptor DNA-binding domain.

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Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism Triplet repeat expansion
Disease	Disease mutation Neurodegeneration
Domain	Zinc-finger
Ligand	DNA-binding Lipid-binding Metal-binding Steroid-binding Zinc
Molecular function	Activator Receptor
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	cell death Inferred from electronic annotation. Source: UniProtKB-KW cell growth Non-traceable author statement. Source: UniProtKB cell proliferation Ref.22 Non-traceable author statement. Source: UniProtKB cell-cell signaling Traceable author statement. Source: ProtInc prostate gland development Ref.22 Non-traceable author statement. Source: UniProtKB transcription, DNA-dependent Inferred from direct assay. Source: UniProtKB transport Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Inferred from direct assay. Source: UniProtKB nucleus Inferred from direct assay. Source: UniProtKB
Molecular function	androgen binding Ref.22 Non-traceable author statement. Source: UniProtKB androgen receptor activity Ref.12 Ref.22 Traceable author statement. Source: UniProtKB protein dimerization activity Ref.22 Non-traceable author statement. Source: UniProtKB receptor binding Inferred from physical interaction. Source: UniProtKB transcription factor activity Inferred from direct assay. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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With	Entry	#Exp.	IntAct	Notes
ADAM10	O14672	1	EBI-608057,EBI-1536151
CTNNB1	P35222	1	EBI-608057,EBI-491549
DAXX	Q9UER7	2	EBI-608057,EBI-77321
DDC	P20711	1	EBI-608057,EBI-1632155
FOXO1	Q12778	1	EBI-608057,EBI-1108782
Foxo1	Q9R1E0	1	EBI-608057,EBI-1371343	From a different organism.
HIF1A	Q16665	1	EBI-608057,EBI-447269
JMJD1C	Q15652	1	EBI-608057,EBI-1224969
MDM2	Q00987	1	EBI-608057,EBI-389668
MYST2	O95251	3	EBI-608057,EBI-473199
NCOA2	Q15596	1	EBI-608057,EBI-81236
NCOA4	Q13772	1	EBI-608057,EBI-954501
NCOA6	Q14686	1	EBI-608057,EBI-78670
PA2G4	Q9UQ80	1	EBI-608057,EBI-924893
PARK7	Q99497	5	EBI-608057,EBI-1164361
PRDX1	Q06830	2	EBI-608057,EBI-353193

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Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Chain

1 – 919

919

Androgen receptor

PRO_0000053704

DNA binding

559 – 631

Nuclear receptor

Zinc finger

559 – 579

NR C4-type

Zinc finger

595 – 619

NR C4-type

Region

1 – 558

558

Modulating

Region

571 – 661

Interaction with HIPK3 By similarity

Region

624 – 919

296

Interaction with MYST2

Region

690 – 919

230

Ligand-binding

Compositional bias

54 – 57

Poly-Leu

Compositional bias

58 – 89

Gln-rich

Compositional bias

58 – 78

Poly-Gln

Compositional bias

84 – 89

Poly-Gln

Compositional bias

193 – 197

Poly-Gln

Compositional bias

372 – 381

Poly-Pro

Compositional bias

396 – 402

Poly-Ala

Compositional bias

449 – 472

Poly-Gly

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P10275-1)

Also known as: AR-B;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P10275-2)

Also known as: AR-A; Variant AR45;

The sequence of this isoform differs from the canonical sequence as follows:
1-531: Missing.
532-538: GPYGDMR → MILWLHS

Binding site

705

Androgen

Binding site

752

Androgen

Binding site

877

Androgen

Site

720

Interaction with coactivator LXXL motif

Site

897

Interaction with coactivator FXXLF motif