title: Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif.
abstract: 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.
authors: From the Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
authors: Katja
authors: K
authors: Jehle
authors: Laura
authors: L
authors: Cato
authors: Antje
authors: A
authors: Neeb
authors: Claudia
authors: C
authors: Muhle-Goll
authors: Nicole
authors: N
authors: Jung
authors: Emmanuel W
authors: EW
authors: Smith
authors: Victor
authors: V
authors: Buzon
authors: Laia R
authors: LR
authors: Carbó
authors: Eva
authors: E
authors: Estébanez-Perpiñá
authors: Katja
authors: K
authors: Schmitz
authors: Ljiljana
authors: L
authors: Fruk
authors: Burkhard
authors: B
authors: Luy
authors: Yu
authors: Y
authors: Chen
authors: Marc B
authors: MB
authors: Cox
authors: Stefan
authors: S
authors: Bräse
authors: Myles
authors: M
authors: Brown
authors: Andrew C B
authors: AC
authors: Cato
mesh_terms: D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D009842:Oligopeptides; D011944:Receptors, Androgen; D014157:Transcription Factors
keywords: Activation Function-2 (AF-2); Androgen Receptor; Androgen Receptor Ligand-binding Domain (AR-LBD); Bag-1L; Binding Function-3 (BF-3); Chromatin Immunoprecipitation (ChiP); Gene Expression; Ligand-binding Protein; Nuclear Receptors; Prostate Cancer