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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:
It is part of: Science Advances, 2022, vol. 9, num. 11, p. 1-26
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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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