Site-specific phosphorylation induces functionally active conformation in the intrinsically disordered N-terminal activation function (AF1) domain of the glucocorticoid receptor.
Intrinsically disordered (ID) regions are disproportionately higher in cell signaling proteins and are predicted to have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. In this study, we show that AF1, an ID activation domain of the glucocorticoid receptor (GR), adopts a functionally folded conformation due to its site-specific phosphorylation by p38 mitogen-activated protein kinase, which is involved in apoptotic and gene-inductive events initiated by the GR. Further, we show that site-specific phosphorylation-induced secondary and tertiary structure formation specifically facilitates AF1's interaction with critical coregulatory proteins and subsequently its transcriptional activity. These data demonstrate a mechanism through which ID activation domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions.
Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Anna M S
AM
Garza
Shagufta H
SH
Khan
Raj
R
Kumar
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D035181:TATA-Box Binding Protein / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D035181:TATA-Box Binding Protein; D050882:CREB-Binding Protein; D056920:Nuclear Receptor Coactivator 1; D048051:p38 Mitogen-Activated Protein Kinases