Mammalian protein found in humans
AR
Available structures
PDB Ortholog search:
PDBe
RCSB List of PDB id codes
1E3G ,
1GS4 ,
1T5Z ,
1T63 ,
1T65 ,
1XJ7 ,
1XOW ,
1XQ3 ,
1Z95 ,
2AM9 ,
2AMA ,
2AMB ,
2AO6 ,
2AX6 ,
2AX7 ,
2AX8 ,
2AX9 ,
2AXA ,
2HVC ,
2OZ7 ,
2PIO ,
2PIP ,
2PIQ ,
2PIR ,
2PIT ,
2PIU ,
2PIV ,
2PIW ,
2PIX ,
2PKL ,
2PNU ,
2Q7I ,
2Q7J ,
2Q7K ,
2YHD ,
2YLO ,
2YLP ,
2YLQ ,
2Z4J ,
3B5R ,
3B65 ,
3B66 ,
3B67 ,
3B68 ,
3BTR ,
3V49 ,
3V4A ,
3ZQT ,
4HLW ,
3L3X ,
3L3Z ,
3RLJ ,
3RLL ,
4K7A ,
4OEA ,
4OED ,
4OEY ,
4OEZ ,
4OFR ,
4OFU ,
4OGH ,
4OH5 ,
4OH6 ,
4OHA ,
4OIL ,
4OIU ,
4OJ9 ,
4OJB ,
4OK1 ,
4OKB ,
4OKT ,
4OKW ,
4OKX ,
4OLM ,
4QL8 ,
5CJ6
Identifiers
Aliases
AR , AIS, AR8, DHTR, HUMARA, HYSP1, KD, NR3C4, SBMA, SMAX1, TFM, androgen receptorExternal IDs
OMIM :
313700 ;
MGI :
88064 ;
HomoloGene :
28 ;
GeneCards :
AR ;
OMA :
AR - orthologs
Wikidata
Androgen_recep
crystal structure of the human androgen receptor ligand binding domain bound with an androgen receptor nh2-terminal peptide, ar20-30, and r1881
Symbol Androgen_recep
Pfam
PF02166
InterPro
IPR001103
Normal function of the androgen receptor. Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestosterone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat-shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.
[5]
[6]
[7]
[8]
The androgen receptor (AR ), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of
nuclear receptor
[9] that is activated by binding any of the
androgenic
hormones , including
testosterone and
dihydrotestosterone ,
[10] in the
cytoplasm and then translocating into the
nucleus . The androgen receptor is most closely related to the
progesterone receptor , and
progestins in higher dosages can block the androgen receptor.
[11]
[12]
The main function of the androgen receptor is as a
DNA-binding
transcription factor that
regulates gene expression ;
[13] however, the androgen receptor has other functions as well.
[14] Androgen-regulated genes are critical for the development and maintenance of the male sexual
phenotype .
Function
Effect on development
In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by
5-alpha-reductase to dihydrotestosterone, an even more potent
agonist for androgen receptor activation.
[15] Testosterone appears to be the primary androgen receptor-activating hormone in the
Wolffian duct , whereas dihydrotestosterone is the main androgenic hormone in the
urogenital sinus ,
urogenital tubercle , and
hair follicles .
[16] Testosterone is therefore responsible primarily for the development of male
primary sexual characteristics , whilst dihydrotestosterone is responsible for
secondary male characteristics .
Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from the
estrogen produced by
aromatization of androgens.
Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in
androgen insensitivity syndrome or
estrogen insensitivity syndrome .
[17]
Knockout-mice studies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of the
ovarian follicles and
ovulation , working through both intra-ovarian and
neuroendocrine mechanisms.
[18]
Maintenance of male skeletal integrity
Via the androgen receptor, androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling can be attributed to both
osteoblasts and
osteocytes .
[19]
Role in females
The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR
knockout female mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation of
trabecular bone structure is a result of DNA-binding-dependent actions of the AR in females.
Moreover, the importance of understanding female androgen receptors lies in their role in several genetic disorders including androgen insensitivity syndrome (AIS).
Complete (CAIS) and
partial (PAIS) which are a result of
mutations in the genes that code for AR. These mutations cause the inactivation of AR due to mutations conferring resistance to circulating testosterone, with more than 400 different AR mutations reported.[
citation needed ]
Mechanism of action
Genomic
The primary mechanism of action for androgen receptors is
direct regulation of
gene transcription .
Androgens (also called androgenic hormones), such as testosterone or dihydrotestosterone, are understood to exert their primary effects through binding to an androgen receptor in the cytosol. The receptor is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via androgen responsive elements.
[20] This androgen response mechanism is perhaps best known and characterized in the context of male sexual differentiation and puberty, but plays a role in a variety of tissue types and processes.
[21]
[22] Upon binding to androgens, the androgen receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen-responsive genes.
[23]
The binding of an androgen to the androgen receptor results in a
conformational change in the receptor that, in turn, causes dissociation of
heat shock proteins , transport from the
cytosol into the
cell nucleus , and
dimerization . The androgen receptor dimer binds to a specific sequence of DNA known as a
hormone response element , where it forms macromolacular protein condensates that might facilitate rapid gene regulation as consequence of local high protein concentrations together with other coregulators.
[24] Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific
gene transcription.
[25] Up-regulation or activation of transcription results in increased synthesis of
messenger RNA , which, in turn, is translated by
ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the
insulin-like growth factor 1 receptor (IGF-1R).
[26] Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.
One function of androgen receptor that is independent of direct binding to its target DNA sequence is facilitated by recruitment via other
DNA-binding proteins . One example is
serum response factor , a protein that activates several genes that cause muscle growth.
[27]
Androgen receptor is modified by
post-translational modification through
acetylation ,
[28] which directly promotes AR-mediated
transactivation ,
apoptosis
[29] and contact-independent growth of
prostate cancer cells.
[30] AR acetylation is induced by androgens
[31] and determines recruitment into
chromatin .
[32] The AR acetylation site is a key target of
NAD -dependent and
TSA -dependent
histone deacetylases
[33] and
long non-coding RNA .
[34]
Non-genomic
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other
steroid hormone receptors such as
estrogen receptors , androgen receptors can have actions that are independent of their interactions with DNA.
[14]
[35] Androgen receptors interact with certain
signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in
ion transport . Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.
Genetics
Gene
In humans, the androgen receptor is encoded by the AR
gene located on the
X chromosome at Xq11–12.
[36]
[37]
Deficiencies
At least 165 disease-causing mutations in this gene have been discovered.
[38] The
androgen insensitivity syndrome , formerly known as testicular feminization, is caused by a mutation in the androgen receptor gene on the
X chromosome (locus: Xq11–Xq12).
[39] The androgen receptor seems to affect neuron physiology and is defective in
Kennedy's disease .
[40]
[41] In addition,
point mutations and
trinucleotide repeat
polymorphisms have been linked to a number of additional disorders.
[42]
CAG repeats
The AR gene contains
CAG repeats that affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists,
[43]
[44] with African-Americans having fewer repeats than non-Hispanic white Americans.
[43] The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these two groups.
Mutations
The
enhancer and the gene encoding for these receptors contain recurrent mutations, such as structural rearrangements and copy number changes, acquired in the progression of metastatic castration-resistant prostate cancer (mCRPC) treatment with therapy targeting these receptors (abiraterone,
enzalutamide ), make the disease progression determined by the androgen receptor genotype.
[45]
Structure
Structural domains of the two isoforms (AR-A and AR-B ) of the human androgen receptor. Numbers above the bars refer to the amino acid residues that separate the domains starting from the N-terminus (left) to C-terminus (right). NTD = N-terminal domain, DBD = DNA-binding domain, LBD = ligand-binding domain, AF = activation function.
Isoforms
Two
isoforms of the androgen receptor (A and B ) have been identified:
[46]
Domains
Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional
domains labeled A through F :
[48]
A/B ) – N-terminal is a regulatory domain which is intrinsically disordered that
[49] contains:
[50]
Dimerization surface involving residues 1–36, the 23 FQNLF27 motif
[51] (B only ) nd 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular
[52]
[53]
[54] head-to-tail interaction
[55]
[56]
[57]
Polyglutamine repeat
[58] (AR-B only)
Transactivation unit 1 (TAU-1) between residues 101 and 370 required for full
ligand -activated transcriptional activity
[59]
Trans
activation unit 5 (TAU-5) between residues 360–485 is responsible for the
constitutive activity (activity without bound ligand)
[59]
C ) –
DNA binding domain (DBD)
Contains two Zinc fingers
[60]
D ) – Hinge region; flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent
nuclear localization signal
[61]
E ) – Ligand binding domain (LBD) containing
activation function 2 (AF-2), responsible for agonist induced activity (activity in the presence of bound agonist)
AF-2 binds either the N-terminal FXXFL motif
intramolecularly or
coactivator proteins (containing the LXXLL or preferably FXXFL motifs)
[57]
A ligand dependent
nuclear export signal
[62]
F ) –
C-terminal domain
Splice variants
AR-V7 is an androgen receptor
splice variant that can be detected in
circulating tumor cells of metastatic
prostate cancer patients
[63]
[64] and is predictive of resistance to some drugs.
[65]
Clinical significance
High expression in androgen receptor has been linked to aggression and sex drive by affecting the HPA and HPG axis
[66]
Aberrant androgen receptor
coregulator activity may contribute to the progression of
prostate cancer .
[67]
[45]
Ligands
Agonists
Endogenous
androgens (e.g.,
testosterone ,
dihydrotestosterone ,
androstenedione ,
androstenediol ,
dehydroepiandrosterone )
Synthetic
androgens (e.g.,
methyltestosterone ,
metandienone ,
nandrolone ,
trenbolone ,
oxandrolone ,
stanozolol )
Mixed
Antagonists
Steroidal antiandrogens (e.g.,
cyproterone acetate ,
chlormadinone acetate ,
spironolactone ,
oxendolone )
Nonsteroidal antiandrogens (e.g.,
flutamide ,
nilutamide ,
bicalutamide ,
enzalutamide ,
apalutamide ,
RU-58841 )
N-Terminal domain antiandrogens (e.g.,
bisphenol A ,
EPI-001 ,
ralaniten , JN compounds)
[69]
As a drug target
The AR is an important therapeutic target in
prostate cancer . Thus many different
antiandrogens have been developed, primarily targeting the
ligand-binding domain of the protein.
[70] AR
ligands can either be classified based on their structure (
steroidal or
nonsteroidal ) or based on their ability to activate or inhibit transcription (
agonists or
antagonists ).
[71] Inhibitors that target alternative functional domains (
N-terminal domain ,
DNA-binding domain ) of the protein are still under development.
[69]
Drug resistance
Alteration of ARs may lead to treatment resistance (castration resistance) in prostate cancer as there may be
missense mutations of the
ligand binding domain , amplifications of the gene coding for this receptor or in its enhancer, mostly, suggesting the presence of different subclones with different genotypes of these receptors.
[45]
Interactions
Androgen receptor has been shown to
interact with:
AKT1 ,
[72]
BAG1 ,
[73]
[74]
[75]
Beta-catenin ,
[76]
[77]
[78]
[79]
[80]
[81]
BRCA1 ,
[82]
[83]
C-jun ,
[84]
Calmodulin 1 ,
[85]
Caveolin 1 ,
[86]
CDK9 ,
[87]
COX5B ,
[88]
CREB-binding protein ,
[89]
[90]
[91]
[92]
Cyclin D1 ,
[93]
[94]
[95]
[96]
Cyclin-dependent kinase 7 ,
[97]
DACH1 ,
[98]
Death associated protein 6 ,
[99]
L-DOPA ,
[100]
EFCAB6 ,
[101]
Epidermal growth factor receptor ,
[102]
[103]
FOXO1 ,
[104]
GAPDH ,
[105]
Gelsolin ,
[106]
GNB2L1 ,
[107]
GSK3B ,
[108]
HDAC1 ,
[109]
HSP90AA1 ,
[110]
[111]
HTATIP ,
[109]
MAGEA11 ,
[112]
[113]
MED1 ,
[114]
MYST2 ,
[115]
NCOA1 ,
[77]
[116]
[117]
NCOA2 ,
[76]
[91]
[112]
[118]
[119]
NCOA3 ,
[118]
[120]
[121]
NCOA4 ,
[72]
[119]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
NCOA6 ,
[129]
NCOR2 ,
[76]
[130]
[131]
NONO ,
[91]
p300 ,
[132]
PA2G4 ,
[133]
PAK6 ,
[134]
[135]
PATZ1 ,
[136]
PIAS2 ,
[137]
[138]
PRPF6 ,
[139]
PTEN ,
[140]
RAD9A ,
[141]
RANBP9 ,
[142]
RCHY1 ,
[143]
Retinoblastoma protein ,
[144]
[145]
RNF14 ,
[119]
[122]
[146]
[147]
RNF4 ,
[136]
[148]
[149]
SART3 ,
[150]
SIRT1 ,
[33]
SMAD3 ,
[151]
[152]
[153]
Small heterodimer partner ,
[154]
Src ,
[140]
[155]
[156]
SRY ,
[157]
STAT3 ,
[158]
[159]
SVIL ,
[160]
Testicular receptor 2 ,
[161]
Testicular receptor 4 ,
[162]
TGFB1I1 ,
[122]
[163]
TMF1 ,
[164]
TRIM68 ,
[165]
UBE2I ,
[76]
[77]
[166]
[167]
[168]
[169]
UXT ,
[170] and
ZMIZ1 .
[171]
See also
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b
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Further reading
External links
(1) Basic domains
(1.1) Basic
leucine zipper (
bZIP )(1.2) Basic helix-loop-helix (
bHLH )
Group A Group B Group C bHLH-
PAS Group D Group E Group F bHLH-COE
(1.3)
bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(2)
Zinc finger DNA-binding domains
(2.1)
Nuclear receptor (Cys4 )
subfamily 1 subfamily 2 subfamily 3 subfamily 4 subfamily 5 subfamily 6 subfamily 0
(2.2) Other Cys4 (2.3) Cys2 His2 (2.4) Cys6 (2.5) Alternating composition (2.6) WRKY
(4) β-Scaffold factors with minor groove contacts
(0) Other transcription factors
AR Tooltip Androgen receptor
Agonists
SARMs Tooltip Selective androgen receptor modulator Antagonists
GPRC6A