Dataset Information

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 etiology 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 harbors 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 newly 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.

INSTRUMENT(S): LTQ FT

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Marta Vilaseca

LAB HEAD: Marta Vilaseca Casas

PROVIDER: PXD005575 | Pride | 2018-10-26

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2306_MN_BMOE_3.RAW	Raw
	2306_MN_BMOE_3_chymo_2H2O.zhrs	Other
	2306_MN_BMOE_3_chymo_H2O.zhrs	Other
	2306_MN_Results.xlsx	Xlsx

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Publications

Structure of the homodimeric androgen receptor ligand-binding domain.

Nadal Marta M Prekovic Stefan S Gallastegui Nerea N Helsen Christine C Abella Montserrat M Zielinska Karolina K Gay Marina M Vilaseca Marta M Taulès Marta M Houtsmuller Adriaan B AB van Royen Martin E ME Claessens Frank F Fuentes-Prior Pablo P Estébanez-Perpiñá Eva E

Nature communications 20170206

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-Å<sup>2</sup> larg ...[more]

PMID: 28165461

Similar Datasets

Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.