GRIP1 mediates the interaction between the amino- and carboxyl-termini of the androgen receptor

Howard C. Shen, Grant Buchanan, Lisa M. Butler, Jennifer Prescott, Michael Henderson, Wayne D. Tilley, Gerhard A. Coetzee

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

The androgen receptor (AR) mediates transactivation of target genes by acting as a dimer in which its amino-terminal domain (AR-NTD) interacts with its carboxyl-terminal, ligand-binding domain (AR-LBD) (N/C interaction). Here we assessed if and how AR N/C interaction relates to AR transactivation activity and how the p160 coactivator GRIP1 participates in both processes. The concentration of dihydrotestosterone needed for half-maximal N/C interaction was approximately 10-fold higher than for half-maximal transactivation, indicating a disparity between the two processes. Although a mutation of an LXXLL-like motif, 23FQNLF2723FQNAA27, in the AR-NTD abolished AR N/C interaction, it could be restored by the co-expression of the coactivator GRIP1. Co-expression of mutated forms of GRIP1, possessing alterations known to abolish either of the two AR interaction domains, could not restore AR N/C interaction, suggesting that wild-type GRIP1 normally bridges the two AR domains. Although AR transactivation activity can proceed without AR N/C interaction, we propose that part of the GRIP1 coactivation activity resides in its ability to bind both AR-NTD and -LBD, to stabilize the N/C complex and allow for secondary cofactors to be recruited more efficiently. Our results also indicate that AR N/C interaction enhances but is not necessary for AR transactivation activity.

Original languageEnglish
Pages (from-to)69-74
Number of pages6
JournalBiological Chemistry
Volume386
Issue number1
DOIs
Publication statusPublished or Issued - Jan 2005

Keywords

  • Androgen receptor
  • Coactivator
  • Dimerization
  • Domain interactions
  • Transactivation
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

Cite this