Androgen receptor: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 13: | Line 13: | ||
===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 <ref name="Structure" />, 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 <ref name="Bench to Bedside" />. | DBD is a cysteine-rich region that is the most highly conserved one of the steroid hormone nuclear receptor family <ref name="Structure" />, 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 <ref name="Bench to Bedside" />. | ||
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 <ref name="Structure" /> | 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 <ref name="Structure" />, 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 <ref name="AR" />. | ||
Each DBD monomer has a core composed of two zinc finger motifs, which consists of four cysteine residues that coordinate a zinc ion <ref name="Structure" />. 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 <ref name="AR" />. | Each DBD monomer has a core composed of two zinc finger motifs, which consists of four cysteine residues that coordinate a zinc ion <ref name="Structure" />. 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 <ref name="AR" />. | ||
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 <ref name="AR" />. 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 <ref name="Structure" />. | 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 <ref name="AR" />. 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 <ref name="Structure" />. | ||
| Line 36: | Line 36: | ||
'''[[Image:Translocation.jpg | thumb | upright=1.5]]''' | '''[[Image:Translocation.jpg | thumb | upright=1.5]]''' | ||
In the absence of ligand, the AR is in the cytoplasm and associated with heat-shock and other chaperone proteins. Testosterone is converted into DHT by 5α-reductase, with higher affinity to bind AR. When DHT binds AR, it displaces heat shock proteins, drives the interaction between the N and C terminal, and binds importin-α to translocate the ligand/AR complex into the nucleus. | In the absence of ligand, the AR is in the cytoplasm and associated with heat-shock and other chaperone proteins. Testosterone is converted into DHT by 5α-reductase, with higher affinity to bind AR. When DHT binds AR, it displaces heat shock proteins, drives the interaction between the N and C terminal, and binds importin-α to translocate the ligand/AR complex into the nucleus. | ||
In the nucleus, the receptor dimerizes and binds to AREs in the promoter regions of target genes. At the promoter, the AR is able to recruit members of the basal transcription machinery in addition to other coregulators to facilitate transcription <ref name="Structure" />. AR activity is not only regulated by ligand binding and DNA binding but also by intramolecular interactions between functional domains, by homodimerization and by interactions with cofactors | In the nucleus, the receptor dimerizes and binds to AREs in the promoter regions of target genes. At the promoter, the AR is able to recruit members of the basal transcription machinery in addition to other coregulators to facilitate transcription <ref name="Structure" />. AR activity is not only regulated by ligand binding and DNA binding but also by intramolecular interactions between functional domains, by homodimerization and by interactions with cofactors <ref>PMID: 22328501</ref>. | ||
This leads to the initiation of transcription, cell proliferation and survival, and negative feedback to inactivate AR transcription <ref name="Bench to Bedside" />. | This leads to the initiation of transcription, cell proliferation and survival, and negative feedback to inactivate AR transcription <ref name="Bench to Bedside" />. | ||
