Structural studies of an androgen receptor complex reveal modes of allosteric regulation Meeting Abstract
| Authors: | Wasmuth, E. V.; Vanden Broeck, A.; LaClair, J.; Lawrence, K. E.; Hoover, E. A.; Pappas, K.; Wang, B.; Manova-Todorova, K.; Weintraub, S. T.; Klinge, S.; Sawyers, C. L. |
| Abstract Title: | Structural studies of an androgen receptor complex reveal modes of allosteric regulation |
| Meeting Title: | Experimental Biology 2022 |
| Abstract: | The androgen receptor (AR) is the master transcription factor governing gene expression programs required for prostate epithelium development and male phenotype maintenance. AR misregulation is a hallmark of prostate cancer where AR hyperactivation and transcriptome expansion occur in part through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR's domains and cofactors cooperate to bind DNA have remained elusive. We isolated three conformations of AR bound to DNA showing AR forms a non-obligate dimer, with the buried dimer interface utilized by ancestral steroid receptors repurposed to facilitate cooperative DNA binding. We identify novel allosteric surfaces which are compromised in androgen insensitivity syndrome, and reinforced by AR's oncoprotein cofactor, ERG, and DNA binding motifs. Finally, we present evidence this plastic dimer interface was adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR's cooperative interactions translate to consequences in development and disease. © FASEB. |
| Journal Title: | FASEB Journal |
| Volume: | 36 |
| Issue: | Suppl. 1 |
| Meeting Dates: | 2022 Apr. 2-5 |
| Meeting Location: | Philadelphia, PA |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2022-05-01 |
| Language: | English |
| DOI: | 10.1096/fasebj.2022.36.S1.R2062 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 1 June 2022 -- Source: Scopus |
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