title: Influence of domain interactions on conformational mobility of the progesterone receptor detected by hydrogen/deuterium exchange mass spectrometry.
abstract: Structural and functional details of the N-terminal activation function 1 (AF1) of most nuclear receptors are poorly understood due to the highly dynamic intrinsically disordered nature of this domain. A hydrogen/deuterium exchange (HDX) mass-spectrometry-based investigation of TATA box-binding protein (TBP) interaction with various domains of progesterone receptor (PR) demonstrate that agonist-bound PR interaction with TBP via AF1 impacts the mobility of the C-terminal AF2. Results from HDX and other biophysical studies involving agonist- and antagonist-bound full-length PR and isolated PR domains reveal the molecular mechanism underlying synergistic transcriptional activation mediated by AF1 and AF2, dominance of PR-B isoform over PR-A, and the necessity of AF2 for full AF1-mediated transcriptional activity. These results provide a comprehensive picture elaborating the underlying mechanism of PR-TBP interactions as a model for studying nuclear receptor (NR)-transcription factor functional interactions.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Devrishi
authors.initials: D
authors.lastname: Goswami
authors.affiliation: Departments of Molecular and Cellular Biology and Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Celetta
authors.initials: C
authors.lastname: Callaway
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Pascal
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18510, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Departments of Molecular and Cellular Biology and Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: pgriffin@scripps.edu.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D041961:Deuterium Exchange Measurement; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods*; D015735:Mifepristone / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011397:Promegestone / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D035181:TATA-Box Binding Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011980:Receptors, Progesterone; D035181:TATA-Box Binding Protein; C509817:TBP protein, human; D015735:Mifepristone; D011397:Promegestone