+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Site-specific phosphorylation induces functionally active conformation in the intrinsically disordered N-terminal activation function (AF1) domain of the glucocorticoid receptor



Site-specific phosphorylation induces functionally active conformation in the intrinsically disordered N-terminal activation function (AF1) domain of the glucocorticoid receptor



Molecular and Cellular Biology 30(1): 220-230



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 055803570

Download citation: RISBibTeXText

PMID: 19841061

DOI: 10.1128/mcb.00552-09


Related references

Trehalose induces functionally active conformation in the intrinsically disordered N-terminal domain of glucocorticoid receptor. Journal of Biomolecular Structure and Dynamics 35(10): 2248-2256, 2016

Naturally occurring osmolyte, trehalose induces functional conformation in an intrinsically disordered activation domain of glucocorticoid receptor. Plos One 6(5): E19689, 2011

A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain. Biochimica et Biophysica Acta. General Subjects 1862(6): 1452-1461, 2018

A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain. Biochimica et Biophysica Acta - General Subjects 1862(6): 1452-1461, 2018

Role of Phosphorylation in the Modulation of the Glucocorticoid Receptor's Intrinsically Disordered Domain. Biomolecules 9(3), 2019

Thermodynamic dissection of the intrinsically disordered N-terminal domain of human glucocorticoid receptor. Journal of Biological Chemistry 287(32): 26777-26787, 2012

Binding of the N-terminal region of coactivator TIF2 to the intrinsically disordered AF1 domain of the glucocorticoid receptor is accompanied by conformational reorganizations. Journal of Biological Chemistry 287(53): 44546-44560, 2013

Nucleosome linker DNA contacts and induces specific folding of the intrinsically disordered H1 carboxyl-terminal domain. Molecular and Cellular Biology 31(11): 2341-2348, 2011

Osmolyte-induced folding of an intrinsically disordered activation function subdomain of glucocorticoid receptor. Journal of Receptor and Signal Transduction Research 28(5): 465-474, 2008

Effects of phosphorylation on the structure and backbone dynamics of the intrinsically disordered connexin43 C-terminal domain. Journal of Biological Chemistry 288(34): 24857-24870, 2013

An NMR study on the intrinsically disordered core transactivation domain of human glucocorticoid receptor. Bmb Reports 50(10): 522-527, 2017

Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activation by glycogen synthase kinase-3 (GSK-3). Species-specific differences between human and rat glucocorticoid receptor signaling as revealed through GSK-3 phosphorylation. Journal of Biological Chemistry 273(23): 14315-14321, 1998

The N-terminal domain of unknown function (DUF959) in collagen XVIII is intrinsically disordered and highly O-glycosylated. Biochemical Journal 475(22): 3577-3593, 2018

Assessing induced folding within the intrinsically disordered C-terminal domain of the Henipavirus nucleoproteins by site-directed spin labeling EPR spectroscopy. Journal of Biomolecular Structure and Dynamics 31(5): 453-471, 2013

Solution structure of the C-terminal X domain of the measles virus phosphoprotein and interaction with the intrinsically disordered C-terminal domain of the nucleoprotein. Journal of Molecular Recognition 23(5): 435-447, 2010