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Homologous steroid receptors assemble at identical promoter architectures with unique energetics of cooperativity



Steroid receptors comprise a homologous family of ligand-activated transcription factors. The receptors bind largely identical response elements in vitro, yet regulate distinct gene networks in vivo. This paradox raises the issue of how transcriptional specificity is achieved, particularly if multiple receptor populations are competing for identical sites. Noting that receptor-DNA energetics are a primary force in driving transcriptional activity, differences in interaction energetics among the receptors might underlie receptor-specific transcriptional control. Thermodynamic dissections support this premise—upon assembling at an identical promoter architecture, individual receptors exhibit vast differences in cooperative and self-association energetics. More intriguingly, these parameters distribute in a way that mirrors the evolutionary divergence of the steroid receptor family. For example, the closely related progesterone and glucocorticoid receptors (PR and GR) display little or no self-association but strong intersite cooperativity, whereas the more distantly related estrogen receptor (ER-α) shows inverse behavior. These findings suggest that receptors view genomic promoter architectures as a collection of affinity landscapes; receptors select from this landscape via their unique interaction energetics. To test this idea, we analyzed the cooperative binding energetics of the above three receptors using an array of promoters. We find that cooperativity is not only receptor-specific but also highly promoter-specific. Thus PR shows maximal cooperativity at promoters with closely spaced and in phase binding sites. GR cooperativity is maintained over greater distances, is larger energetically, and shows markedly different phase dependency. Finally, ER-α appears incapable of cooperativity regardless of promoter architecture, consistent with its more distant phylogeny. Proteins 2014; 82:2078–2087. © 2014 Wiley Periodicals, Inc.