Sandbox
The androgen receptor (AR) belongs to the steroid hormone group nuclear receptor family with the estrogen, progesterone, glucocorticoid and mineralcorticoid receptor. AR mediate the actions of testosterone (T) and a more biologically active form, 5α-dihydrotestosterone (DHT), which are the male sex hormones required for development of the male reproductive system and secondary sexual characteristics. This receptor, located on the X chromosome, is expressed in a diverse range of tissues, because they have significant biological actions in many systems [1]. There are other androgens that bind with much less potency than T and DHT such as androstenedione, androstenediol, and dehydroepiandrosterone (DHEA) [2].
StructureStructure
Like members of the nuclear receptor family, the AR consists of three main functional domains which aid in controlling and regulating transcriptional activity.
DomainsDomains
N-terminal Domain (NTD)(residues 1-555)N-terminal Domain (NTD)(residues 1-555)
This region is required for full transcriptional activity [3], because of its necessary presence for LBD activation [4]. It is the most variable domain, the sequence and lengths of the polyglutamine (CAG) and polyglycine (GGC) repeats are highly variable in the human population. It has been shown that the length of the polyglutamine repeat region affects the folding and structure of this domain, shorter repeats generally impose a higher AR transactivation activity, whereas longer repeats cause reduced activity [5]. In healthy people, one region of the AR gene shows up to 36 repeats of the CAG sequence. Patients with abnormally high numbers of CAG repeats can develop spinal muscular atrophy.
DNA-binding Domain (DBD) (residues 555-623)DNA-binding Domain (DBD) (residues 555-623)
DBD is a cysteine-rich region that is the most highly conserved one of the steroid hormone nuclear receptor family [6], but it has been shown that binding of selective androgen response elements (AREs) allow the specific activation functions of the AR. They facilitate direct DNA binding of the AR to the promoter and enhancer regions of AR-regulated genes, thereby allowing the activation functions of the N-terminal and ligand binding domains to stimulate or repress the transcription of these genes [7]. AR is a dimer, like other steroid receptors, that binds to promoter DNA response elements consisting of two equal, common hexameric half-sites, separated by a 3 base-pair spacer [8]IMAGEN DEL DÍMERO, and this domain is critical for AR function, because it plays a role in dimerization and binding of dimerized AR to select motifs on target DNA [9]. Each DBD monomer has a core composed of two zinc finger motifs, which consists of four cysteine residues that coordinate a zinc ion [10]. The first is closer to the NTD which has the P box, which is identical in all the family, and controls the DNA binding specificity at AREs, located in the regulatory regions of genes [11]. The second zinc finger motif facilitates AR dimerization via the D box. Additionally, a nuclear localization signal (NLS) is localized at the junction between the DBD and the hinge region and it binds to importin-α and facilitates nuclear translocation [12]. This is because passive transport across the nuclear pore complex has been suggested ranging from 20–40 kDa, in contrast, the AR, which is 110 kDa in size, requires help to be actively transported upon ligand binding [13]. The DBD is linked to the ligand binding domain by a flexible hinge region (residues 623-665), which is a linker poorly conserved. Once in the nucleus, this region also interacts with the DBD to identify specific sequences for AR binding. It controls the AR activation and degradation. Consequently, mutations in the hinge region can lead to enhanced AR potency [14].
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