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Androgen_recep
crystal structure of the human androgen receptor ligand binding domain bound with an androgen receptor nh2-terminal peptide, ar20-30, and r1881
The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of
nuclear receptor[5] that is activated by binding of either of the
androgenic hormones
testosterone or
dihydrotestosterone[6] 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.[7][8]
The main function of the androgen receptor is as a DNA-binding
transcription factor that regulates gene expression;[9] however, the androgen receptor has other functions as well.[10] 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.[11] 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.[12] Hence, testosterone is responsible primarily for the development of male
primary sexual characteristics, whereas dihydrotestosterone is responsible for
secondary male characteristics.
Androgens cause slow
epiphysis, or maturation of the bones, but more of the potent
epiphysis 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.[13]
Also, AR
knockout-mice studies have shown that AR 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.[14]
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. [15]
Mechanism of action
Genomic
The primary mechanism of action for androgen receptors is direct regulation of
gene transcription. 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. Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific
genetranscription.[16] 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 I receptor (
IGF-1R).[17] 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.[18]
Androgen receptor is modified by acetylation, which directly promotes contact independent growth of prostate cancer cells.[19]
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.[10][20] 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 ARgene located on the
X chromosome at Xq11-12.[21][22]
AR deficiencies
The
androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation of the androgen receptor gene located on the X chromosome (locus:Xq11-Xq12).[23]
The androgen receptor seems to affect neuron physiology and is defective in
Kennedy's disease.[24][25] In addition, point mutations and trinucleotide repeat polymorphisms has been linked to a number of additional disorders.[26]
Structure
Isoforms
Two
isoforms of the androgen receptor (A and B) have been identified:[27]
AR-A - 87
kDa - N-terminus truncated (lacks the first 187 amino acids), which results from in vitro proteolysis.[28]
AR-B - 110 kDa - full length
Domains
Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional
domains labeled A through F:[29]
activation function 1 (AF-1) between residues 101 and 370 required for full ligand activated transcriptional activity
activation function 5 (AF-5) between residues 360-485 is responsible for the constitutive activity (activity without bound ligand)
dimerization surface involving residues 1-36 (containing the FXXLF motif where F =
phenylalanine, L =
leucine, and X = any amino acid residue) and 370-494, both of which interact with the LBD in an intramolecular[31][32][33] head-to-tail interaction[34][35][36]
D) - Hinge region - flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent
nuclear localization signal[37]
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