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Structure of the homodimeric androgen receptor ligand-binding domain

Author

Listed:
  • Marta Nadal

    (Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
    Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)
    Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau))

  • Stefan Prekovic

    (Molecular Endocrinology Laboratory, KU Leuven)

  • Nerea Gallastegui

    (Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
    Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR))

  • Christine Helsen

    (Molecular Endocrinology Laboratory, KU Leuven)

  • Montserrat Abella

    (Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
    Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR))

  • 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
    Erasmus Optical Imaging Centre, Erasmus MC)

  • Martin E. van Royen

    (Erasmus MC
    Erasmus Optical Imaging Centre, 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)
    Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau))

  • Eva Estébanez-Perpiñá

    (Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
    Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR))

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.

Suggested Citation

  • Marta Nadal & Stefan Prekovic & Nerea Gallastegui & Christine Helsen & Montserrat Abella & Karolina Zielinska & Marina Gay & Marta Vilaseca & Marta Taulès & Adriaan B. Houtsmuller & Martin E. van Roye, 2017. "Structure of the homodimeric androgen receptor ligand-binding domain," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14388
    DOI: 10.1038/ncomms14388
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