Phosphorylation of Glucocorticoid Receptor tau1c Transactivation Domain Enhances Binding to CREB Binding Protein (CBP) TAZ2 and a Microfluidic, High Throughput Protein Crystal Growth Method for Microgravity



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The glucocorticoid receptor (GR) N-terminal domain (NTD) contains a transactivation domain (activation function 1; AF-1). Although GR AF-1 is phosphorylated, effects of GR phosphorylation upon AF-1 activity and cofactor recruitment are not clear. Most GR AF-1 activity is confined to an unstructured domain called tau1c (amino acids 187-244) that contains three phosphorylation sites and binds to a cysteine rich fragment (CH3) of the co-activator CREB binding protein (CBP). Because CH3 overlaps the CBP transcriptional adaptor zinc binding (TAZ) 2 domain, implicated in phosphorylation dependent binding to other unstructured transcription factor domains, we investigated if GR interacts with TAZ2 and whether this binding event is modulated by phosphorylation. We find that GR tau1c is required for enhancement of GR function and GR/CBP association in cultured cells. Tau1c interacts with TAZ2 in vitro with reasonable affinity and peptide mapping reveals CBP binding determinants throughout tau1c. Phosphorylation at GR S203, not involved in transactivation, does not affect tau1c binding to TAZ2. However, phosphorylation at S211 and S226, markers of GR transcriptional activity, enhances TAZ2 binding in a synergistic fashion. We propose that GR tau1c phosphorylation could promote CBP recruitment and enhance AF-1 activity.



Phosphorylation, Glucocorticoids, Glucocorticoid receptors, Tau1c, Transactivation, CBP, Transcriptional adaptor zinc binding (TAZ) 2


Portions of this document appear in: Carruthers, Carl W., Ji Ho Suh, Jan-Ake Gustafsson, and Paul Webb. "Phosphorylation of glucocorticoid receptor tau1c transactivation domain enhances binding to CREB binding protein (CBP) TAZ2." Biochemical and biophysical research communications 457, no. 1 (2015): 119-123. And in: Carruthers Jr, Carl W., Cory Gerdts, Michael D. Johnson, and Paul Webb. "A microfluidic, high throughput protein crystal growth method for microgravity." PloS one 8, no. 11 (2013): e82298.