The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor.
Androgens drive sex differentiation, bone and muscle development, and promote growth of hormone-dependent cancers by binding the nuclear androgen receptor (AR), which recruits coactivators to responsive genes. Most nuclear receptors recruit steroid receptor coactivators (SRCs) to their ligand binding domain (LBD) using a leucine-rich motif (LXXLL). AR is believed to recruit unique coactivators to its LBD using an aromatic-rich motif (FXXLF) while recruiting SRCs to its N-terminal domain (NTD) through an alternate mechanism. Here, we report that the AR-LBD interacts with both FXXLF motifs and a subset of LXXLL motifs and that contacts with these LXXLL motifs are both necessary and sufficient for SRC-mediated AR regulation of transcription. Crystal structures of the activated AR in complex with both recruitment motifs reveal that side chains unique to the AR-LBD rearrange to bind either the bulky FXXLF motifs or the more compact LXXLL motifs and that AR utilizes subsidiary contacts with LXXLL flanking sequences to discriminate between LXXLL motifs.
Estébanez-Perpiñá
Eva
E
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.
Moore
Jamie M R
JM
Mar
Ellena
E
Delgado-Rodrigues
Edson
E
Nguyen
Phuong
P
Baxter
John D
JD
Buehrer
Benjamin M
BM
Webb
Paul
P
Fletterick
Robert J
RJ
Guy
R Kiplin
RK
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D004583:Electrons; D015723:Gene Library; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry*; D015533:Transcriptional Activation; D014162:Transfection
D008024:Ligands; D010455:Peptides; D011944:Receptors, Androgen; D008156:Luciferases; D005982:Glutathione Transferase; D007930:Leucine