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Mol Endocrinol. 1995 Feb;9(2):208-18.

Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability.

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1
Department of Pediatrics, University of North Carolina, Chapel Hill 27599, USA.

Abstract

The molecular basis for the different physiological effects of testosterone (T) and dihydrotestosterone (DHT) was investigated using recombinantly expressed wild-type and mutant androgen receptor (AR). Rates of androgen dissociation from nuclear and cytoplasmic AR were compared with hormone- and concentration-dependent receptor degradation rates. T dissociates from AR 3 times faster than DHT or methyltrienolone (R1881) and is less effective in stabilizing the receptor. Analysis of AR deletion mutants and AR/glucocorticoid receptor chimeras indicates that the AR NH2-terminal domain has a specific role in stabilizing the receptor by slowing the rate of ligand dissociation and AR degradation. Amino acid mutations that abolish receptor dimerization, nuclear localization, or DNA-binding activity have no significant effect on androgen dissociation or AR degradation. A naturally occurring steroid-binding domain mutation (Val889 to Met) that causes androgen insensitivity, but does not alter equilibrium androgen binding affinity, lowered the androgen-binding capacity as a result of increased rates of androgen dissociation and AR degradation. Thus, AR stabilization and function require prolonged receptor occupancy with androgen, with a similar extent of stabilization observed at higher concentrations of faster dissociating androgens and lower concentrations of slower dissociating androgens. Retention of receptor-bound androgen is enhanced by an interaction between the AR NH2-terminal and steroid-binding domains. The ligand specificity and concentration dependence of receptor stabilization provide an explanation for physiological differences in the actions of T and DHT.

PMID:
7776971
DOI:
10.1210/mend.9.2.7776971
[Indexed for MEDLINE]

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