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Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif
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The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.
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JEHLE, Katja, CATO, Laura, NEEB, Antje, MUHLE-GOLL, Claudia, JUNG, Nicole, SMITH, Emmanuel w., BUZÓN REDORTA, Víctor, CARBÓ, Laia r., ESTÉBANEZ PERPIÑÁ, Eva, SCHMITZ, Katja, FRUK, Ljiljana, CHEN, Yu, COX, Marc b., BRASE, Stefan, BROWN, Myles, CATO, Andrew c. b.. Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif. _Journal of Biological Chemistry_. 2014. Vol. 289, núm. 13, pàgs. 8839-8851. [consulta: 21 de gener de 2026]. ISSN: 0021-9258. [Disponible a: https://hdl.handle.net/2445/53357]