Structural Basis for Androgen Receptor Interdomain and Coactivator Interactions Suggests a Transition in Nuclear Receptor Activation Function Dominance

Abstract

The androgen receptor (AR) is required for male sex development and contributes to prostate cancer cell survival. In contrast to other nuclear receptors that bind the LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound FXXLF and LXXLL peptides. Key residues that establish motif binding specificity are identified through comparative structure-function and mutagenesis studies. A mechanism in prostate cancer is suggested by a functional AR mutation at a specificity-determining residue that recovers coactivator LXXLL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion and functional dominance of the NH(2)-terminal transactivation domain in the steroid receptor subfamily.

Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

“…Evaluation of the crystallographic structure of a peptide containing the LXXLL sequence bound to AR shows that the LXXLL motif adopts an a-helical structure and that the side chains of the three leucines at the i, i þ 3 and i þ 4 positions interact with the hydrophobic pocket in the AF2 domain of AR 24,25 . We used the rigid and pre-organized structure of a bis-benzamide scaffold 26 to design the peptidomimetic D2 that mimics the LXXLL motif and disrupts the interaction between AR and NR box containing proteins such as PELP1 (Fig.…”

“…NATURE COMMUNICATIONS | DOI: 10.1038/ncomms2912 ARTICLE Discussion AR requires interactions with its coregulator proteins to actively engage in transcriptional activity 31,32 . Given that many coregulators interact with the AR through motifs containing the consensus LXXLL motif 24 , where L is Leucine and X is any amino acid, we rationally designed peptidomimetics that imitate the LXXLL motif with the aim of disrupting necessary AR-mediated PPIs and thereby inhibit AR signalling and the survival of prostate cancer cells. Previous attempts to generate LXXLL-based peptide drugs have been unsuccessful, predominantly due to issues with cell permeability and degradation.…”

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

“…Like other nuclear receptors (NRs), AR is a transcription factor regulating target-gene expression in a liganddependent manner (2,16). Cognate ligand binding induces conformational changes predominantly in helix 12 of AR LBD, which enhances transcriptional activity by forming a liganddependent AF-2 binding interface for coactivators (17). Wilson and colleagues demonstrated that the interdomain interaction between AF-1 in NTD and AF-2 in LBD (N/C interaction) leads to AR stabilization and slower ligand dissociation (18,19).…”

Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity

“…In the absence of ligand, AR is located primarily in the cytoplasm as an inactive complex with heat shock proteins. Upon androgen binding, AR undergoes conformational change, translocates into the nucleus, and recruits coactivator complexes for transactivation through direct DNA binding to androgen response elements (AREs) in AR target gene promoters (9,10). As observed in wild-type AR, polyQ-AR mutants reportedly translocate into the nucleus and recruit coactivator complexes to the AREs in a liganddependent manner (11).…”