Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Structure. 2018 Jan 2;26(1):145-152.e3. doi: 10.1016/j.str.2017.11.007. Epub 2017 Dec 7.

Abstract

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.

Keywords: androgen receptor; castration-resistant prostate cancer; intrinsic disorder; protein phosphorylation; protein-protein interactions; transcription; transcription factor IIF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Cloning, Molecular
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • HEK293 Cells
  • Humans
  • Intrinsically Disordered Proteins / chemistry*
  • Intrinsically Disordered Proteins / genetics
  • Intrinsically Disordered Proteins / metabolism
  • Male
  • Models, Molecular
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors, TFII / chemistry*
  • Transcription Factors, TFII / genetics
  • Transcription Factors, TFII / metabolism
  • Transcriptional Activation

Substances

  • AR protein, human
  • Intrinsically Disordered Proteins
  • Receptors, Androgen
  • Recombinant Proteins
  • Transcription Factors, TFII
  • DNA
  • transcription factor TFIIF