A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance

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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/198587
Acceso en línea:https://hdl.handle.net/2445/198587
Access Level:acceso abierto
Palabra clave:Càncer de pròstata
Fixació de proteïnes
Mutació (Biologia)
Prostate cancer
Protein binding
Mutation (Biology)
Descripción
Sumario: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.

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