Structure of the Homodimeric androgen receptor ligand-binding domain

The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-bi...

Descripción completa

Detalles Bibliográficos
Autores: Nadal, Marta, Prekovic, Stefan, Gallastegui, Nerea, Helsen, Christine, Abella, Montserrat, Zielinska, Karolina, Gay, Marina, Vilaseca, Marta, Taulés i Marín, Marta, Houtsmuller, Adriaan B., van Royen, Martin E., Claessens, Frank, Fuentes-Prior, Pablo, Estébanez Perpiñá, Eva
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/108258
Acceso en línea:https://hdl.handle.net/2445/108258
Access Level:acceso abierto
Palabra clave:Receptors d'hormones
Difracció de raigs X
Radiocristal·lografia
Hormone receptors
X-rays diffraction
X-ray crystallography
Descripción
Sumario:The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å2 large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo, and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor.

Similares en LA Referencia