Mutation of histidine 874 in the androgen receptor ligand-binding domain leads to promiscuous ligand activation and altered p160 coactivator interactions.

Abstract

The androgen receptor (AR) signaling pathway is a major therapeutic target in the treatment of prostate cancer. The AR functions as a ligand-activated transcription factor in the presence of the cognate hormone ligands testosterone and dihydrotestosterone (DHT). We have characterized a highly conserved sequence at the C-terminal end of helix 10/11 in the ligand-binding domain (LBD), which is prone to receptor point mutations in prostate cancer. This sequence includes threonine 877 that is involved in hydrogen bonding to the D ring of the steroid molecule and leads to promiscuous ligand activation of the AR when mutated to alanine or serine. A second mutation in this region, H874Y, also results in a receptor protein that has broadened ligand-binding specificity, but retains an affinity for DHT (K(d) = 0.77 nm) similar to that of the wild-type receptor. The structure of the mutant LBD, expressed in Escherichia coli, is not dramatically altered compared with the wild-type AR-LBD in the presence of DHT, but shows a modestly increased sensitivity to protease digestion in the absence of hormone. This mutant AR showed wild-type AR-LBD/N-terminal domain interactions, but significantly enhanced binding and transactivation activity with all three members of the p160 family of coactivator proteins. Together, these phenotypic changes are likely to confer a selective advantage for tumor cells in a low androgen environment resulting from hormone therapy.

• Authors: Jennifer Duff, Iain J McEwan
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 19 Issue 12 Pg. 2943-54 (Dec 2005) ISSN: 0888-8809 [Print] United States
• PMID: 16081517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Nuclear Receptor Coactivator 2
• Receptors, Androgen
• Trans-Activators
• Histidine

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Conserved Sequence
• Escherichia coli (genetics)
• Histidine (genetics)
• Humans
• Ligands
• Male
• Molecular Sequence Data
• Nuclear Receptor Coactivator 2 (metabolism)
• Point Mutation
• Prostatic Neoplasms (genetics)
• Protein Interaction Mapping
• Protein Structure, Tertiary
• Receptors, Androgen (chemistry, genetics, metabolism)
• Trans-Activators (metabolism)