Intra-domain Communication Between the N-Terminal and DNA-binding Domains of the Androgen Receptor: Modulation of Androgen Response Element DNA Binding.

Jacqueline Brodie, Iain Joseph McEwan

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised - non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein-base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.

Original languageEnglish
Pages (from-to)603-615
Number of pages12
JournalJournal of Molecular Endocrinology
Volume34
DOIs
Publication statusPublished - 2005

Keywords

  • ESTROGEN-RECEPTOR
  • GLUCOCORTICOID-RECEPTORS
  • ALLOSTERIC MODULATION
  • GENE-EXPRESSION
  • AMINO-ACIDS
  • CONFORMATION
  • PROTEIN
  • SPECIFICITY
  • REGION
  • IDENTIFICATION

Cite this

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title = "Intra-domain Communication Between the N-Terminal and DNA-binding Domains of the Androgen Receptor: Modulation of Androgen Response Element DNA Binding.",
abstract = "The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised - non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein-base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.",
keywords = "ESTROGEN-RECEPTOR, GLUCOCORTICOID-RECEPTORS, ALLOSTERIC MODULATION, GENE-EXPRESSION, AMINO-ACIDS, CONFORMATION, PROTEIN, SPECIFICITY, REGION, IDENTIFICATION",
author = "Jacqueline Brodie and McEwan, {Iain Joseph}",
year = "2005",
doi = "10.1677/jme.1.01723",
language = "English",
volume = "34",
pages = "603--615",
journal = "Journal of Molecular Endocrinology",
issn = "0952-5041",
publisher = "Society for Endocrinology",

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TY - JOUR

T1 - Intra-domain Communication Between the N-Terminal and DNA-binding Domains of the Androgen Receptor: Modulation of Androgen Response Element DNA Binding.

AU - Brodie, Jacqueline

AU - McEwan, Iain Joseph

PY - 2005

Y1 - 2005

N2 - The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised - non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein-base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.

AB - The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised - non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein-base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.

KW - ESTROGEN-RECEPTOR

KW - GLUCOCORTICOID-RECEPTORS

KW - ALLOSTERIC MODULATION

KW - GENE-EXPRESSION

KW - AMINO-ACIDS

KW - CONFORMATION

KW - PROTEIN

KW - SPECIFICITY

KW - REGION

KW - IDENTIFICATION

U2 - 10.1677/jme.1.01723

DO - 10.1677/jme.1.01723

M3 - Article

VL - 34

SP - 603

EP - 615

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

SN - 0952-5041

ER -