Genetic variations within the ERE motif modulate plasticity and energetics of binding of DNA to the ER? nuclear receptor.

ABSTRACT: Upon binding to estrogens, the ER? nuclear receptor acts as a transcription factor and mediates a multitude of cellular functions central to health and disease. Herein, using isothermal titration calorimetry (ITC) and circular dichroism (CD) in conjunction with molecular modeling (MM), we analyze the effect of symmetric introduction of single nucleotide variations within each half-site of the estrogen response element (ERE) on the binding of ER? nuclear receptor. Our data reveal that ER? exudes remarkable tolerance and binds to all genetic variants in the physiologically relevant nanomolar-micromolar range with the consensus ERE motif affording the highest affinity. We provide rationale for how genetic variations within the ERE motif may reduce its affinity for ER? by orders of magnitude at atomic level. Our data also suggest that the introduction of genetic variations within the ERE motif allows it to sample a much greater conformational space. Surprisingly, ER? displays no preference for binding to ERE variants with higher AT content, implying that any advantage due to DNA plasticity may be largely compensated by unfavorable entropic factors. Collectively, our study bears important consequences for how genetic variations within DNA promoter elements may fine-tune the physiological action of ER? and other nuclear receptors.

SUBMITTER: Deegan BJ 

PROVIDER: S-EPMC3044919 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature