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Title: Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif
Author: Jehle, K.
Cato, L.
Neeb, A.
Muhle-Goll, C.
Jung, N.
Smith, Emmanuel W.
Buzón Redorta, Victor
Carbó, L. R.
Estébanez Perpiñá, Eva
Schmitz, K.
Fruk, L.
Chen, Y.
Cox, Marc B.
Brase, S.
Brown, M.
Cato, Andrew C. B.
Keywords: Receptors nuclears (Bioquímica)
Càncer de pròstata
Nuclear receptors (Biochemistry)
Prostate cancer
Issue Date: 12-Feb-2014
Publisher: American Society for Biochemistry and Molecular Biology
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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Biological Chemistry, 2014, vol. 289, num. 13, p. 8839-8851
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ISSN: 0021-9258
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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