Flowchart: Preparation: AF-1








Text Box: IDText Box: Af-1






Text Box: GR

Text Box: DBD                                 




Mol Cell Biol. 2010 Jan;30(1):220-30.

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

Garza AM, Khan SH, Kumar R.

Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.


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.

PMID: 19841061 [PubMed

Arch Biochem Biophys. 2010 Apr 15;496(2):140-5. Epub 2010 Feb 25.

Influence of flanking sequences on signaling between the activation function AF1 and DNA-binding domain of the glucocorticoid receptor.

Kumar R, Thompson EB.

Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18510, USA. rkumar@tcmedc.org


Despite their importance in gene regulation, the exact mechanisms of glucocorticoid receptor's (GR's) N-terminal activation function region, AF1, which exists in an intrinsically disordered (ID) conformation remains largely unknown. For its interaction with critical coregulatory proteins, AF1 must be malleable and capable of presenting varied interaction surfaces. We hypothesize that various confluences of effects, including intra-molecular signaling between the AF1 and the GR DNA-binding domain (DBD) cause functional structure to form in AF1. In this study, we tested the effect of the amino acid sequences surrounding AF1 on the propensity of AF1 to gain structure when connected to DBD. Removal of amino acids between AF1 and DBD results in the formation of more ordered conformation in AF1. In addition, sequences flanking the AF1 may play an inhibitory role in AF1 activity. These results suggest a mechanism as to why certain GR isoforms with truncated N-terminal domains show altered transcriptional activity. 2010 Elsevier Inc. All rights reserved.

PMID: 20188692 [