Structure of the homodimeric androgen receptor ligand-binding domain

Marta Nadal, Stefan Prekovic, Nerea Gallastegui, Christine Helsen, Montserrat Abella, Karolina Zielinska, Marina Gay, Marta Vilaseca, Marta Taulès, Adriaan B. Houtsmuller, Martin E. van Royen, Frank Claessens, Pablo Fuentes-Prior () and Eva Estébanez-Perpiñá ()
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Marta Nadal: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
Stefan Prekovic: Molecular Endocrinology Laboratory, KU Leuven
Nerea Gallastegui: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
Christine Helsen: Molecular Endocrinology Laboratory, KU Leuven
Montserrat Abella: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
Karolina Zielinska: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
Marina Gay: Mass Spectrometry Core Facility, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST)
Marta Vilaseca: Mass Spectrometry Core Facility, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST)
Marta Taulès: Unitat de Citometria, Centres Científics I Tecnològics (CCIT), Universitat de Barcelona (UB)
Adriaan B. Houtsmuller: Erasmus MC
Martin E. van Royen: Erasmus MC
Frank Claessens: Molecular Endocrinology Laboratory, KU Leuven
Pablo Fuentes-Prior: Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)
Eva Estébanez-Perpiñá: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14388

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