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-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-Å2large 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.
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona 08028, Spain.|Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Barcelona 08010, Spain.|Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08025, Spain.
Marta
M
Nadal
Molecular Endocrinology Laboratory, KU Leuven, Herestraat 49, Leuven 3000, Belgium.
Stefan
0000-0002-7051-9321
S
Prekovic
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona 08028, Spain.|Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Barcelona 08010, Spain.
Nerea
N
Gallastegui
Molecular Endocrinology Laboratory, KU Leuven, Herestraat 49, Leuven 3000, Belgium.
Christine
0000-0003-1048-2798
C
Helsen
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona 08028, Spain.|Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Barcelona 08010, Spain.
Montserrat
M
Abella
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona 08028, Spain.
Karolina
K
Zielinska
Mass Spectrometry Core Facility, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain.
Marina
M
Gay
Mass Spectrometry Core Facility, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain.
Marta
M
Vilaseca
Unitat de Citometria, Centres Científics I Tecnològics (CCIT), Universitat de Barcelona (UB), Barcelona 08028, Spain.
Marta
M
Taulès
Department of Pathology, Erasmus MC, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.|Erasmus Optical Imaging Centre, Erasmus MC, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
Adriaan B
AB
Houtsmuller
Department of Pathology, Erasmus MC, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.|Erasmus Optical Imaging Centre, Erasmus MC, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
Martin E
ME
van Royen
Molecular Endocrinology Laboratory, KU Leuven, Herestraat 49, Leuven 3000, Belgium.
Frank
0000-0002-8676-7709
F
Claessens
Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Barcelona 08010, Spain.|Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08025, Spain.
Pablo
P
Fuentes-Prior
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona 08028, Spain.|Bases Estructurals de Processos Fisiopatològics Fonamentals, 2014-SGR-01214, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Barcelona 08010, Spain.
Eva
E
Estébanez-Perpiñá
D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000235:genetics*; D000072417:Protein Domains / Q000235:genetics*; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D044764:Ubiquitin-Activating Enzymes / Q000737:chemistry / Q000378:metabolism
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000728:Androgens; D008024:Ligands; D011944:Receptors, Androgen; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human