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; Eva Estébanez-Perpiñá

doi:10.1038/ncomms14388

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^*, Eva Estébanez-Perpiñá^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	14388
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14388
Publication status	Published - 6 Feb 2017
Externally published	Yes

Keywords

Androgen Receptor Antagonists/pharmacology
Androgen-Insensitivity Syndrome/genetics
Androgens/metabolism
Animals
COS Cells
Cell Line, Tumor
Chlorocebus aethiops
Crystallography, X-Ray
Humans
Ligands
Male
Models, Molecular
Point Mutation
Prostatic Neoplasms/genetics
Protein Domains/genetics
Protein Multimerization/drug effects
Protein Structure, Quaternary/drug effects
Receptors, Androgen/genetics
Surface Plasmon Resonance
Ubiquitin-Activating Enzymes/chemistry

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Nadal, M., Prekovic, S., Gallastegui, N., Helsen, C., Abella, M., Zielinska, K., Gay, M., Vilaseca, M., Taulès, M., Houtsmuller, A. B., van Royen, M. E., Claessens, F., Fuentes-Prior, P., & Estébanez-Perpiñá, E. (2017). Structure of the homodimeric androgen receptor ligand-binding domain. Nature Communications, 8, Article 14388. https://doi.org/10.1038/ncomms14388

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title = "Structure of the homodimeric androgen receptor ligand-binding domain",

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-{\AA} crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-{\AA}2 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.",

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author = "Marta Nadal and Stefan Prekovic and Nerea Gallastegui and Christine Helsen and Montserrat Abella and Karolina Zielinska and Marina Gay and Marta Vilaseca and Marta Taul{\`e}s and Houtsmuller, {Adriaan B} and {van Royen}, {Martin E} and Frank Claessens and Pablo Fuentes-Prior and Eva Est{\'e}banez-Perpi{\~n}{\'a}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = feb,

day = "6",

doi = "10.1038/ncomms14388",

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T1 - Structure of the homodimeric androgen receptor ligand-binding domain

AU - Nadal, Marta

AU - Prekovic, Stefan

AU - Gallastegui, Nerea

AU - Helsen, Christine

AU - Abella, Montserrat

AU - Zielinska, Karolina

AU - Gay, Marina

AU - Vilaseca, Marta

AU - Taulès, Marta

AU - Houtsmuller, Adriaan B

AU - van Royen, Martin E

AU - Claessens, Frank

AU - Fuentes-Prior, Pablo

AU - Estébanez-Perpiñá, Eva

N1 - Publisher Copyright: © The Author(s) 2017.

PY - 2017/2/6

Y1 - 2017/2/6

N2 - 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.

AB - 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.

KW - Androgen Receptor Antagonists/pharmacology

KW - Androgen-Insensitivity Syndrome/genetics

KW - Androgens/metabolism

KW - Animals

KW - COS Cells

KW - Cell Line, Tumor

KW - Chlorocebus aethiops

KW - Crystallography, X-Ray

KW - Humans

KW - Ligands

KW - Male

KW - Models, Molecular

KW - Point Mutation

KW - Prostatic Neoplasms/genetics

KW - Protein Domains/genetics

KW - Protein Multimerization/drug effects

KW - Protein Structure, Quaternary/drug effects

KW - Receptors, Androgen/genetics

KW - Surface Plasmon Resonance

KW - Ubiquitin-Activating Enzymes/chemistry

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U2 - 10.1038/ncomms14388

DO - 10.1038/ncomms14388

M3 - Article

C2 - 28165461

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14388

ER -

Structure of the homodimeric androgen receptor ligand-binding domain

Abstract

Keywords

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