Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/198587
Title: | A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance |
Author: | Alegre-Martí, Andrea Jiménez Panizo, Alba Martínez-Tébar, Adrián Poulard, Coralie Peralta Moreno, María Nuria Abella, Montserrat Antón, Rosa Chiñas, Marcos Eckhard, Ulrich Piulats, Josep M. Rojas, Ana M. Fernández Recio, Juan Rubio Martínez, Jaime Le Romancer, Muriel Aytés Meneses, Álvaro Fuentes-Prior, Pablo Estébanez Perpiñá, Eva |
Keywords: | Càncer de pròstata Fixació de proteïnes Mutació (Biologia) Prostate cancer Protein binding Mutation (Biology) |
Issue Date: | 5-Dec-2022 |
Publisher: | American Association for the Advancement of Science |
Abstract: | Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine. |
Note: | Reproducció del document publicat a: https://doi.org/10.1126/sciadv.ade2175 |
It is part of: | Science Advances, 2022, vol. 9, num. 11, p. 1-26 |
URI: | http://hdl.handle.net/2445/198587 |
Related resource: | https://doi.org/10.1126/sciadv.ade2175 |
ISSN: | 2375-2548 |
Appears in Collections: | Articles publicats en revistes (Ciència dels Materials i Química Física) Articles publicats en revistes (Bioquímica i Biomedicina Molecular) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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