Architectural principles for the structure and function of the glucocorticoid receptor tau 1 core activation domain

A 58-amino acid region mediates the core transactivation activity of the gl ucocorticoid receptor tau 1 activation domain. This tau 1 core domain is un structured in aqueous buffers, but in the presence of trifluoroethanol thre e or-helical segments are induced. Two of these putative structural modules have been tested in different combinations with regard to transactivation potential in vivo and binding capacity to the coactivators in vitro, The re sults show that whereas single modules are not transcriptionally active, an y combination of two or three modules is sufficient, with trimodular constr ucts having the highest activity. However, proteins containing one, two, or three segments bind Ada2 and cAMP-response element-binding protein with si milar affinity. A single segment is thus able to bind a target factor but c annot transactivate target genes significantly. The results are consistent with models in which activation domains are comprised of short activation m odules that allow multiple interactions with coactivators. Our results also suggest that an increased number of modules may not result in correspondin gly higher affinity but instead that the concentration of binding sites is increased, which gives rise to a higher association rate. This is consisten t with a model where the association rate for activator-target factor inter actions rather than the equilibrium constant is the most relevant measure o f activator potency.