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Binding‐folding induced regulation of the glucocorticoid receptor AF1 transactivation domain by a cofactor that binds to its DNA binding domain
Author(s) -
Khan Shagufta H,
Garza Anna S,
Moure Carmen M,
Edwards Dean P,
Kumar Raj
Publication year - 2010
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.24.1_supplement.857.3
Subject(s) - transactivation , glucocorticoid receptor , microbiology and biotechnology , folding (dsp implementation) , chemistry , receptor , dna binding domain , nuclear receptor , biophysics , biology , biochemistry , gene , gene expression , transcription factor , engineering , electrical engineering
Intrinsically disordered (ID) regions commonly exist within the N‐terminal AF1 activation domains of steroid receptors (SRs). The mechanisms by which SRs pass signals from a steroid hormone to control gene expression remain a central unresolved problem. Role of ID AF1 in this process is of immense importance as it provides platforms (through conditional folding) for interactions of specific co‐regulatory proteins, and thereby dictates the final outcome SR‐regulated target gene expression. However, the means by which AF1 acquires functionally folded conformations is not well understood. It has been suggested that under physiological conditions, inter‐ and intra‐ molecular interactions lead to structure formation in AF1. In this study, we tested whether binding of jun dimerization protein 2 (JDP2) within the DNA binding domain (DBD) of the glucocorticoid receptor (GR) leads to acquisition of an active conformation in AF1. Our results show that signals mediated from GR DBD:JDP2 interactions in a two domain GR fragment, consisting of the N‐terminal domain and DBD (GR500), significantly increased secondary/tertiary structure formation of AF1. This induced structure facilitated AF1’s interaction with specific co‐regulatory proteins, and subsequent GRE‐mediated AF1 activity. These results support the hypothesis that inter‐ and intra‐ molecular signals give a functionally active structure(s) to AF1.