MCB Accepts, published online ahead of print on 19 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00552-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

SITE-SPECIFIC PHOSPHORYLATION INDUCES FUNCTIONALLY ACTIVE CONFORMATION IN THE INTRINSICALLY DISORDERED N-TERMINAL ACTIVATION FUNCTION (AF1) DOMAIN OF THE GLUCOCORTICOID RECEPTOR

Anna MS Garza, Shagufta H. Khan, and Raj Kumar^*

Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX-77555; Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA-18510

^* To whom correspondence should be addressed. Email: rkumar{at}tcmedc.org.

Intrinsically disordered (ID) regions are disproportionately higher in cell signaling proteins and are predicted to have much higher frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. In this study, we have shown that AF1, an ID activation domain of the glucocorticoid receptor (GR) adopts a functionally folded conformation due to its site-specific phosphorylation by p38 MAPK, which is involved in apoptotic and gene-inductive events initiated by GR. Further, we have shown 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 provide 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.