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Osmolyte‐induced folding of an intrinsically disordered transactivation function domain of the Glucocorticoid Receptor
Author(s) -
Khan Shagufta H,
Kumar Raj
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.968.3
Subject(s) - transactivation , glucocorticoid receptor , transcription factor , intrinsically disordered proteins , osmolyte , microbiology and biotechnology , function (biology) , chemistry , folding (dsp implementation) , computational biology , gene , biology , biochemistry , engineering , electrical engineering
To initiate transcription of target gene(s), the glucocorticoid receptor (GR) interacts with its response element DNA, and/or with coregulatory proteins. However, specific interaction surfaces of GR with its coregulators are not well understood. Consequently, precisely how transcription is regulated by GR is largely unknown. This is due, in part, to the lack of structural information about GR's major activation function region, AF1, which exists in an intrinsically disordered (ID) conformation. It is believed that ID nature of AF1 promotes molecular recognition by creating large interaction surfaces suitable for interactions with its coregulatory proteins. It has been hypothesized that conditional folding of AF1 domain may be a prerequisite for their efficient interaction with specific coregulatory proteins, and subsequent transcriptional activity leading to the regulation of target gene(s). In this study, we tested whether naturally occurring osmolytes can promote functionally ordered conformation in the GR's AF1 domain. Our data show that AF1 adopts a functionally active ordered conformation in the presence of osmolyte such that AF1's interaction with specific coregulatory proteins and its subsequent transcriptional activity is significantly enhanced. Our results may provide a mechanism by which AF1 mediates the target‐specific gene regulation by GR. Supported by a grant from NIH (DK058829).