GRIP1 mediates the interaction between the amino- and carboxyl-termini of the androgen receptor.
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, 23 FQNLF 27 --> 23 FQNAA 27 , 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.
Shen
Howard C
HC
Departments of Urology and Preventive Medicine, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Buchanan
Grant
G
Butler
Lisa M
LM
Prescott
Jennifer
J
Henderson
Michael
M
Tilley
Wayne D
WD
Coetzee
Gerhard A
GA
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D013196:Dihydrotestosterone / Q000494:pharmacology; D005786:Gene Expression Regulation; D008024:Ligands; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D014157:Transcription Factors; D013196:Dihydrotestosterone