The cell-specific activity of the estrogen receptor alpha may be fine-tuned by phosphorylation-induced structural gymnastics

Abstract

The estrogen receptor alpha (ERalpha) regulates the transcription of target genes by recruiting coregulator proteins through several domains including the two activation functions AF1 and AF2. The contribution of the N-terminally located AF1 activity is particularly important in differentiated cells, and for ERalpha to integrate inputs from other signaling pathways. However, how the phosphorylation of key residues influences AF1 activity has long remained mysterious, in part because the naturally disordered AF1 domain has resisted a structural characterization. The recent discovery of two coregulators that are specific for a phosphorylated form of AF1 suggests that phosphorylation, possibly in conjunction with the subsequent binding of these coregulators, may enforce a stable structure. The binding of the "pioneer" coregulators might facilitate the subsequent recruitment of yet other coregulators. Different AF1 folds may be enabled by the combinatorial action of posttranslational modifications and coregulator binding thereby fine-tuning ERalpha activities in a cell- and promoter-specific fashion.

Figure 1. Coordinated binding of coregulators to AF1 depends on phosphorylation-induced structural changes.

(a) Coregulators facilitate each other's recruitment by stabilizing the specific fold of phosphorylated AF1. (b) Binding of one coregulator stabilizes a particular AF1 structure and allows the subsequent recruitment of another coregulator. (c) A second coregulator recognizes both the newly induced AF1 structure and coregulator 1.