A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance

Abstract

Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure–function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand–binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg 761 . We also corroborate the relevance of residues Arg 761 and Tyr 764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine.

ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription

“…To further investigate the link between ALDH genes and AR signaling, we correlated the initial preoperative prostate-specific antigen (iPSA) serum level in patients with PCa with protein expression of ALDH1A1 and ALDH1A3 and observed a significantly increased iPSA level in patients with ALDH1A3 overexpressing tumors (Figure 2 G). There was no significant difference in the nuclear AR expression between tumors with or without ALDH1A1 or ALDH1A3 expression ( Figure S2 F), although a transcription program driven by nuclear AR might be repressed or activated depending on the presence of many regulatory proteins 28 . While ALDH1A1 negatively correlates with AR target genes in noncancerous prostate epithelium, this mutual exclusivity reduces upon tumor development.…”

Predicting valuable missense variants with AlphaMissense in a multiple pulmonary infection patient

“…The androgen receptor (AR), with a score of 0.33, belongs to the steroid subfamily of nuclear receptors and plays a crucial role in male development and tissue maintenance. Mutations in AR are associated with the conditions such as prostate cancer 23 . The DNA repair nuclease MRE11A, scoring 0.19, is responsible for maintaining metabolic competence by safeguarding mitochondrial DNA.…”

“…Mutations in AR are associated with the conditions such as prostate cancer. 23 The DNA repair nuclease MRE11A, scoring 0.19, is responsible for maintaining metabolic competence by safeguarding mitochondrial DNA. In cases of rheumatoid arthritis, MRE11A deficiency in T cells disrupted mitochondrial oxygen consumption, leading to suppressed ATP generation.…”