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Allosteric interactions prime androgen receptor dimerization and activation

View ORCID ProfileElizabeth V. Wasmuth, View ORCID ProfileArnaud Vanden Broeck, Justin R. LaClair, Elizabeth A. Hoover, Kayla E. Lawrence, View ORCID ProfileNavid Paknejad, View ORCID ProfileKyrie Pappas, View ORCID ProfileDoreen Matthies, View ORCID ProfileBiran Wang, View ORCID ProfileWeiran Feng, Philip A. Watson, View ORCID ProfileJohn C. Zinder, View ORCID ProfileWouter R. Karthaus, View ORCID ProfileM. Jason de la Cruz, Richard K. Hite, Katia Manova-Todorova, Zhiheng Yu, View ORCID ProfileSusan T. Weintraub, View ORCID ProfileSebastian Klinge, View ORCID ProfileCharles L. Sawyers
doi: https://doi.org/10.1101/2022.02.20.481229
Elizabeth V. Wasmuth
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
2The Rockefeller University, New York, NY, 10065 USA
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  • ORCID record for Elizabeth V. Wasmuth
  • For correspondence: wasmuthe@mskcc.org sawyersc@mskcc.org
Arnaud Vanden Broeck
2The Rockefeller University, New York, NY, 10065 USA
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Justin R. LaClair
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Elizabeth A. Hoover
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Kayla E. Lawrence
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Navid Paknejad
3Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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  • ORCID record for Navid Paknejad
Kyrie Pappas
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Doreen Matthies
4Cryo-Electron Microscopy Facility, Janelia Research Campus, Ashburn, VA, 20147 USA
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Biran Wang
5Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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  • ORCID record for Biran Wang
Weiran Feng
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Philip A. Watson
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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John C. Zinder
2The Rockefeller University, New York, NY, 10065 USA
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Wouter R. Karthaus
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M. Jason de la Cruz
3Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Richard K. Hite
3Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Katia Manova-Todorova
5Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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Zhiheng Yu
4Cryo-Electron Microscopy Facility, Janelia Research Campus, Ashburn, VA, 20147 USA
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Susan T. Weintraub
6Department of Biochemistry and Structural Biology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, 78229, USA
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  • ORCID record for Susan T. Weintraub
Sebastian Klinge
2The Rockefeller University, New York, NY, 10065 USA
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Charles L. Sawyers
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
7Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA
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  • ORCID record for Charles L. Sawyers
  • For correspondence: wasmuthe@mskcc.org sawyersc@mskcc.org
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Summary

The androgen receptor (AR) is a steroid receptor and master transcription factor that governs gene expression programs required for luminal development of prostate epithelium, formation of muscle tissue and maintenance of the male phenotype. AR misregulation is a hallmark of multiple malignancies, including prostate cancer, where AR hyperactivation and expansion of its transcriptome occur in part through AR gene amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR’s individual domains and its protein cofactors cooperate to bind DNA have remained elusive. Using a combination of reconstitution biochemistry and single particle cryo-electron microscopy (EM), we have isolated three conformational states of AR bound to DNA. We observe that AR forms a non-obligate dimer, with the buried dimer interface utilized by related ancestral nuclear receptors repurposed to facilitate cooperative DNA binding. We identify surfaces bridging AR’s domains responsible for allosteric communication, that are compromised in partial androgen insensitivity syndrome (PAIS), and are reinforced by AR’s oncoprotein cofactor, ERG, and DNA binding site motifs. Finally, we present evidence that this plastic dimer interface for transcriptional activation may have been adopted by AR at the expense of DNA binding. Our work highlights how fine-tuning of AR’s cooperative interactions translate to consequences in development and disease.

Competing Interest Statement

Dr. Sawyers serves on the Board of Directors of Novartis, is a co-founder of ORIC Pharmaceuticals and co-inventor of enzalutamide and apalutamide. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra and PMV. He was a co-founder of Seragon, purchased by Genentech/Roche in 2014.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 21, 2022.
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Allosteric interactions prime androgen receptor dimerization and activation
Elizabeth V. Wasmuth, Arnaud Vanden Broeck, Justin R. LaClair, Elizabeth A. Hoover, Kayla E. Lawrence, Navid Paknejad, Kyrie Pappas, Doreen Matthies, Biran Wang, Weiran Feng, Philip A. Watson, John C. Zinder, Wouter R. Karthaus, M. Jason de la Cruz, Richard K. Hite, Katia Manova-Todorova, Zhiheng Yu, Susan T. Weintraub, Sebastian Klinge, Charles L. Sawyers
bioRxiv 2022.02.20.481229; doi: https://doi.org/10.1101/2022.02.20.481229
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Allosteric interactions prime androgen receptor dimerization and activation
Elizabeth V. Wasmuth, Arnaud Vanden Broeck, Justin R. LaClair, Elizabeth A. Hoover, Kayla E. Lawrence, Navid Paknejad, Kyrie Pappas, Doreen Matthies, Biran Wang, Weiran Feng, Philip A. Watson, John C. Zinder, Wouter R. Karthaus, M. Jason de la Cruz, Richard K. Hite, Katia Manova-Todorova, Zhiheng Yu, Susan T. Weintraub, Sebastian Klinge, Charles L. Sawyers
bioRxiv 2022.02.20.481229; doi: https://doi.org/10.1101/2022.02.20.481229

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