[en] The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA has remained elusive. Using single-particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that 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 by DNA-binding motifs. Finally, we present evidence that this plastic dimer interface may have been 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Wasmuth, Elizabeth V; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA, Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065, USA. Electronic address: wasmuthe@mskcc.org.
Vanden Broeck, Arnaud ; Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065, USA.
LaClair, Justin R; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Hoover, Elizabeth A; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Lawrence, Kayla E; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Paknejad, Navid; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Pappas, Kyrie; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Matthies, Doreen; Cryo-Electron Microscopy Facility, Janelia Research Campus, Ashburn, VA 20147, USA.
Wang, Biran; Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Feng, Weiran; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Watson, Philip A; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Zinder, John C; Laboratory of Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
Karthaus, Wouter R; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
de la Cruz, M Jason; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Hite, Richard K; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Manova-Todorova, Katia; Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Yu, Zhiheng; Cryo-Electron Microscopy Facility, Janelia Research Campus, Ashburn, VA 20147, USA.
Weintraub, Susan T; Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Klinge, Sebastian; Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065, USA.
Sawyers, Charles L; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA, Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: sawyersc@mskcc.org.
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