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Dissection of Androgen Receptor–Promoter Interactions: Steroid Receptors Partition Their Interaction Energetics in Parallel with Their Phylogenetic Divergence

Author:
De Angelis, Rolando W., Yang, Qin, Miura, Michael T., Bain, David L.
Source:
Journal of Molecular Biology 2013 v.425 pp. 4223-4235
ISSN:
0022-2836
Subject:
DNA, binding sites, dimerization, estrogen receptors, glucocorticoid receptors, mineralocorticoid receptors, mutants, phylogeny, progesterone receptors, prostatic neoplasms, transcription (genetics)
Abstract:
Steroid receptors comprise a homologous family of ligand-activated transcription factors. The members include androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and progesterone receptor (PR). Phylogenetic studies demonstrate that AR, GR, MR, and PR are most closely related, falling into subgroup 3C. ER is more distantly related, falling into subgroup 3A. To determine the quantitative basis by which receptors generate their unique transcriptional responses, we are systematically dissecting the promoter-binding energetics of all receptors under a single “standard state” condition. Here, we examine the self-assembly and promoter-binding energetics of full-length AR and a mutant associated with prostate cancer, T877A. We first demonstrate that both proteins exist only as monomers, showing no evidence of dimerization. Although this result contradicts the traditional understanding that steroid receptors dimerize in the absence of DNA, it is fully consistent with our previous work demonstrating that GR and two PR isoforms either do not dimerize or dimerize only weakly. Moreover, both AR proteins exhibit substantial cooperativity between binding sites, again as seen for GR and PR. In sharp contrast, the more distantly related ER-α dimerizes so strongly that energetics can only be measured indirectly, yet cooperativity is negligible. Thus, homologous receptors partition their promoter-binding energetics quite differently. Moreover, since receptors most closely related by phylogeny partition their energetics similarly, such partitioning appears to be evolutionarily conserved. We speculate that such differences in energetics, coupled with different promoter architectures, serve as the basis for generating receptor-specific promoter occupancy and thus function.
Agid:
5511244