Structure of the homodimeric androgen receptor ligand-binding domain
Por:
Nadal, M, Prekovic, S, Gallastegui, N, Helsen, C, Abella, M, Zielinska, K, Gay, M, Vilaseca, M, Taules, M, Houtsmuller, AB, van Royen, ME, Claessens, F, Fuentes-Prior, P, Estebanez-Perpina, E
Publicada:
6 feb 2017
Resumen:
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-angstrom crystal structure of homodimeric, agonist-and coactivator peptide-bound AR-LBD unveils a 1,000-angstrom 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.
Filiaciones:
Nadal, M:
Univ Barcelona, Inst Biomed IBUB, Dept Biochem & Mol Biomed, E-08028 Barcelona, Spain
AGAUR, Bases Estruct Proc Fisiopatol Fonamentals, 2014 SGR 01214, Barcelona 08010, Spain
Biomed Res Inst St Pau IIB St Pau, Mol Bases Dis, Barcelona 08025, Spain
Prekovic, S:
Katholieke Univ Leuven, Mol Endocrinol Lab, Herestr 49, B-3000 Leuven, Belgium
Gallastegui, N:
Univ Barcelona, Inst Biomed IBUB, Dept Biochem & Mol Biomed, E-08028 Barcelona, Spain
AGAUR, Bases Estruct Proc Fisiopatol Fonamentals, 2014 SGR 01214, Barcelona 08010, Spain
Helsen, C:
Katholieke Univ Leuven, Mol Endocrinol Lab, Herestr 49, B-3000 Leuven, Belgium
Abella, M:
Univ Barcelona, Inst Biomed IBUB, Dept Biochem & Mol Biomed, E-08028 Barcelona, Spain
AGAUR, Bases Estruct Proc Fisiopatol Fonamentals, 2014 SGR 01214, Barcelona 08010, Spain
Zielinska, K:
Univ Barcelona, Inst Biomed IBUB, Dept Biochem & Mol Biomed, E-08028 Barcelona, Spain
Gay, M:
BIST, Inst Res Biomed IRB Barcelona, Mass Spectrometry Core Facil, Barcelona 08028, Spain
Vilaseca, M:
BIST, Inst Res Biomed IRB Barcelona, Mass Spectrometry Core Facil, Barcelona 08028, Spain
Taules, M:
Univ Barcelona, CCIT, Unitat Citometria, E-08028 Barcelona, Spain
Houtsmuller, AB:
Erasmus MC, Dept Pathol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands
Erasmus MC, Erasmus Opt Imaging Ctr, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands
van Royen, ME:
Erasmus MC, Dept Pathol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands
Erasmus MC, Erasmus Opt Imaging Ctr, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands
Claessens, F:
Katholieke Univ Leuven, Mol Endocrinol Lab, Herestr 49, B-3000 Leuven, Belgium
Fuentes-Prior, P:
AGAUR, Bases Estruct Proc Fisiopatol Fonamentals, 2014 SGR 01214, Barcelona 08010, Spain
Biomed Res Inst St Pau IIB St Pau, Mol Bases Dis, Barcelona 08025, Spain
Estebanez-Perpina, E:
Univ Barcelona, Inst Biomed IBUB, Dept Biochem & Mol Biomed, E-08028 Barcelona, Spain
AGAUR, Bases Estruct Proc Fisiopatol Fonamentals, 2014 SGR 01214, Barcelona 08010, Spain
Gold, Green Published
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