Abstract
Intrinsically disordered (ID) regions of the transcription factor proteins have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. Consistent with this phenomenon, most of the functionally known phosphorylation sites in the steroid receptor family of transcription factors are located in the ID N-terminal domain that contains a powerful activation function (AF1) region. In this study, we determined the structural and functional consequences of functionally known phosphorylation residues (Ser203, 211, and 226) located in the human glucocorticoid receptor’s (GR’s) ID AF1 domain. We report the relative importance of each phosphorylation site in inducing a functionally active ordered conformation in GR’s ID AF1 domain. Our data demonstrate a mechanism through which ID domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions.
Highlights
Post-translational modifications such as phosphorylation may regulate protein functions of transcription factors by affecting their conformational dynamics leading to altered transcriptional activities[1,2]
The mechanisms by which glucocorticoid receptor (GR) and other steroid receptors control gene expression pose a central problem in molecular biology and the role of their transcriptional activation domains in this complex process is of immense importance[16]
The GR protein is subject to multiple phosphorylation sites that regulate the function of the receptor[16]
Summary
Post-translational modifications such as phosphorylation may regulate protein functions of transcription factors by affecting their conformational dynamics leading to altered transcriptional activities[1,2]. There are reports suggesting that phosphorylation of Ser[211] may affect GR conformation and alter receptor activity, and AF1 appears to be a main player in this process[7,8,9]. It is not yet known whether other phosphorylation sites (Ser[203] and/or Ser226) influence the structure and functions of the GR AF1. Several studies have suggested that ID regions of the transcription factors have much higher frequency of known phosphorylation sites than ordered regions[1,17,18,19] This is true for the ID AF1 domain of steroid hormone receptors[16]. Phosphorylated Ser[203] and 211 are shown forming a hydrogen bond network that is displayed as dots between donor and acceptor atoms
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