کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2196577 1550929 2011 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Dynamics of coregulator-induced conformational perturbations in androgen receptor ligand binding domain
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
Dynamics of coregulator-induced conformational perturbations in androgen receptor ligand binding domain
چکیده انگلیسی

Androgen receptor (AR) coregulators modulate ligand-induced gene expression in a tissue specific manner. The molecular events that follow coactivator binding to AR and the mechanisms that govern the sequence-specific effects of AR coregulators are poorly understood. Using consensus coactivator sequence D11-FxxLF and biophysical techniques, we show that coactivator association is followed by conformational rearrangement in AR ligand binding domain (AR-LBD) that is enthalpically and entropically favorable with activation energy of 29.8 ± 4.2 kJ/mol. Further characterization of ARA70 and SRC3-1 based consensus sequences reveal that each coactivator induces a distinct conformational state in the dihydrotestosterone:AR-LBD:coactivator complex. Complementary computational modeling revealed that coactivator induced specific alterations in the backbone flexibility of AR-LBD distant from the site of coactivator binding and that the intramolecular rearrangements in AR-LBD backbone induced by the two coactivator peptides were different. These data suggest that coactivators may impart specificity in the transcriptional machinery by changing the steady-state conformation of AR-LBD. These data provide direct evidence that even in the presence of same ligand, AR-LBD can occupy distinct conformational states depending on its interactions with specific coactivators in the tissues. We posit that this coactivator-specific conformational gating may then dictate subsequent binding partners and interaction/affinity for the DNA-response elements.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular and Cellular Endocrinology - Volume 341, Issues 1–2, 20 July 2011, Pages 1–8
نویسندگان
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