Reviewed, UniProtKB/Swiss-Prot P10275 (ANDR_HUMAN)

Names and origin

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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

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

General annotation (Comments)

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.
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.
Subcellular location	Nucleus.
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.
Post-translational modification	Sumoylated on Lys-386 (major) and Lys-520. 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.
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 (AGA) [MIM:109200].
Involvement in disease	Defects in AR are the cause of androgen insensibility syndrome (AIS) [MIM:300068]; previously known as testicular feminization syndrome (TFM). It can be complete (CAIS) when external genitalia are phenotypically female; or partial (PAIS) when external genitalia are substantively ambiguous or mild (MAIS) when external genitalia are normal male or nearly so. Defects in AR are the cause of X-linked spinal and bulbar muscular atrophy (SBMA) [MIM:313200]; also known as Kennedy disease. In SBMA patients the number of Gln ranges from 40 to 52. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. 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 may be the cause of infertility male syndrome [MIM:308370]; also called androgen insensitivity. It is characterized by azoospermia, elevated testosterone and luteinizing hormone plasma levels and an abnormal androgen receptor. Defects in AR are the cause of Reifenstein syndrome [MIM:312300]; also known as partial androgen insensitivity. The features of this form of male pseudohermaphroditism are hypospadias, hypogonadism, gynecomastia, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance.
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.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism Triplet repeat expansion
Disease	Disease mutation
Domain	Zinc-finger
Ligand	DNA-binding Lipid-binding Metal-binding Steroid-binding Zinc
Molecular function	Activator Receptor
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell growth Non-traceable author statement. Source: UniProtKB cell proliferation Ref.19 Non-traceable author statement. Source: UniProtKB cell-cell signaling Traceable author statement. Source: ProtInc prostate gland development Ref.19 Non-traceable author statement. Source: UniProtKB sex differentiation Ref.19 Non-traceable author statement. Source: UniProtKB signal transduction Traceable author statement. Source: ProtInc 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.19 Non-traceable author statement. Source: UniProtKB androgen receptor activity Ref.9 Ref.19 Traceable author statement. Source: UniProtKB protein dimerization activity Ref.19 Non-traceable author statement. Source: UniProtKB receptor binding Inferred from physical interaction. Source: UniProtKB transcription factor activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

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
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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Chain	1 – 919	919	Androgen receptor
Regions
	DNA binding	559 – 631	73	Nuclear receptor
	Zinc finger	559 – 579	21	NR C4-type
	Zinc finger	595 – 619	25	NR C4-type
	Region	1 – 558	558	Modulating
	Region	571 – 661	91	Interaction with HIPK3 By similarity
	Region	624 – 919	296	Interaction with MYST2
	Region	690 – 919	230	Ligand-binding
	Compositional bias	54 – 57	4	Poly-Leu
	Compositional bias	58 – 89	32	Gln-rich
	Compositional bias	58 – 78	21	Poly-Gln
	Compositional bias	84 – 89	6	Poly-Gln
	Compositional bias	193 – 197	5	Poly-Gln
	Compositional bias	372 – 381	10	Poly-Pro
	Compositional bias	396 – 402	7	Poly-Ala
	Compositional bias	449 – 472	24	Poly-Gly
Sites
	Binding site	705	1	Androgen
	Binding site	752	1	Androgen
	Binding site	877	1	Androgen
	Site	720	1	Interaction with coactivator LXXL motif
	Site	897	1	Interaction with coactivator FXXLF motif
Amino acid modifications
	Modified residue	223	1	Phosphotyrosine; by CSK
	Modified residue	267	1	Phosphotyrosine; by CSK
	Modified residue	307	1	Phosphotyrosine; by CSK
	Modified residue	346	1	Phosphotyrosine; by CSK
	Modified residue	357	1	Phosphotyrosine; by CSK
	Modified residue	362	1	Phosphotyrosine; by CSK
	Modified residue	363	1	Phosphotyrosine; by CSK
	Modified residue	393	1	Phosphotyrosine; by CSK
	Modified residue	534	1	Phosphotyrosine; by CSK
	Modified residue	551	1	Phosphotyrosine; by CSK
	Modified residue	915	1	Phosphotyrosine; by CSK
	Cross-link	386		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
	Cross-link	520		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
Natural variations
	Natural variant	2	1	E → K in PAIS.
	Natural variant	54	1	L → S in prostate cancer.
	Natural variant	57	1	L → Q in prostate cancer.
	Natural variant	64	1	Q → R in prostate cancer.
	Natural variant	74 – 78	5	Missing
	Natural variant	112	1	Q → H in prostate cancer.
	Natural variant	180	1	K → R in prostate cancer.
	Natural variant	194	1	Q → R in CAIS.
	Natural variant	205	1	S → R
	Natural variant	214	1	G → R in MAIS; 20% lower transactivation capacity.
	Natural variant	255	1	L → P in CAIS.
	Natural variant	266	1	M → T in prostate cancer.
	Natural variant	269	1	P → S in prostate cancer.
	Natural variant	340	1	P → L in prostate cancer.
	Natural variant	390	1	P → R in CAIS.
	Natural variant	390	1	P → S in MAIS.
	Natural variant	443	1	Q → R in CAIS; might be a polymorphism.
	Natural variant	465 – 472	8	Missing
	Natural variant	491	1	G → S in CAIS.
	Natural variant	528	1	D → G in prostate cancer.
	Natural variant	547	1	L → F in PAIS.
	Natural variant	548	1	P → S in MAIS.
	Natural variant	559	1	C → Y in CAIS.
	Natural variant	568	1	G → V in PAIS.
	Natural variant	568	1	G → W in PAIS.
	Natural variant	571	1	Y → C in CAIS.
	Natural variant	573	1	A → D in CAIS; defective DNA binding and transactivation.
	Natural variant	574	1	L → P in prostate cancer.
	Natural variant	575	1	T → A in prostate cancer.
	Natural variant	576	1	C → F in CAIS; lack of DNA binding.
	Natural variant	576	1	C → R in CAIS.
	Natural variant	579	1	C → F in CAIS; reduced transcription and DNA binding.
	Natural variant	579	1	C → Y in CAIS.
	Natural variant	580	1	K → R in prostate cancer.
	Natural variant	581	1	V → F in CAIS.
	Natural variant	582	1	F → S in PAIS.
	Natural variant	582	1	F → Y in PAIS.
	Natural variant	582	1	Missing in CAIS.
	Natural variant	585	1	R → K in CAIS.
	Natural variant	586	1	A → V in prostate cancer; somatic mutation.
	Natural variant	587	1	A → S in prostate cancer; somatic mutation.
	Natural variant	596	1	A → T in PAIS; abolishes dimerization.
	Natural variant	597	1	S → G in PAIS; high dissociation rate; associated with P-617 in a PAIS patient; partially restores DNA-binding activity of P-617 mutant receptors.
	Natural variant	597	1	S → T in PAIS.
	Natural variant	601	1	C → F in CAIS.
	Natural variant	604	1	D → Y in PAIS.
	Natural variant	607	1	R → Q in PAIS and breast cancer.
	Natural variant	608	1	R → K in PAIS and breast cancer; defective nuclear localization.
	Natural variant	610	1	N → T in PAIS.
	Natural variant	611	1	C → Y in CAIS.
	Natural variant	615	1	R → H in CAIS and PAIS.
	Natural variant	615	1	R → P in CAIS.
	Natural variant	615	1	Missing in CAIS.
	Natural variant	616	1	L → P in CAIS.
	Natural variant	616	1	L → R in PAIS.