Interaction of the Androgen Receptor Ligand-Binding Domain with the N-Terminal Domain and with Coactivators

  • Jan Trapman


The ligand-binding domain of the androgen receptor not only binds ligands, but also contains a ligand-induced protein interaction surface, the cofactor-binding groove. The groove interacts with short amphipatic α-helices in cofactors composed of an FxxLF motif, or with LxxLL motifs at a lower affinity. Moreover, the cofactor-binding groove interacts with an FxxLF motif in the N-terminal domain of the androgen receptor. The groove is able to adapt its shape in complexes with interacting peptides. In the peptide motifs, an F at +1 seems essential for high-affinity binding. L+4 can be replaced by several other hydrophobic amino acid residues without losing activity. Although F at +5 has the highest activity, it can be substituted by tryptophane or tyrosine. Studies of the spatial and temporal distribution of the androgen receptor in the living cell indicates consecutive protein interactions, including intramolecular and intermolecular androgen receptor domain interactions and cofactor binding, depending on the cellular localization.


Amino Acid Residue Androgen Receptor Cyproterone Acetate Peptide Motif Phenylalanine Residue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author is indebted to Martin van Royen and Dennis van de Wijngaart for help with preparation of the manuscript.


  1. Askew EB, Gampe RT, Stanley TB, Faggart JL, Wilson EM. (2007) Modulation of androgen receptor activation function AF2 by testosterone and dihydrotestosterone. J Biol Chem 282:25801–25816.PubMedCrossRefGoogle Scholar
  2. Brooke GN, Parker MG, Bevan CL. (2008) Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression. Oncogene 27:2941–2950.PubMedCrossRefGoogle Scholar
  3. Chang C-Y, Norris JD, Gron H, Paige LA, Hamilton PT, Kenan DJ, Fowlkes D, McDonnell DP. (1999) Dissection of the LxxLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors a and b. Mol Cell Biol 19:8226–8239.PubMedGoogle Scholar
  4. Chang C-Y, Abdo J, Hartney T, McDonnell DP. (2005) Development of peptide antagonsists for the androgen receptor using combinatorial peptide phage display. Mol Endocrinol 19:2478–2490.PubMedCrossRefGoogle Scholar
  5. Doesburg P, Kuil CW, Berrevoets CA, Steketee K, Faber PW, Mulder E, Brinkmann AO, Trapman J. (1997) Functional in vivo interaction between the amino-terminal transactivation domain and the ligand-binding domain of the androgen receptor. Biochemistry 36:1052–1064.PubMedCrossRefGoogle Scholar
  6. Dubbink HJ, Hersmus R, Verma CS, van der Korput HAGM, Berrevoets CA, van Tol J, Ziel-van der Made ACJ, Brinkmann AO, Pike ACW, Trapman J. (2004) Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor. Mol Endocrinol 18:2132–2150.PubMedCrossRefGoogle Scholar
  7. Dubbink HJ, Hersmus R, Pike ACW, Molier M, Brinkmann A, Jenster G, Trapman J. (2006) Androgen receptor ligand-binding domain interaction and nuclear receptor specificity of FXXLF and LXXLL motifs as determined by L/F swapping. Mol Endocrinol 20:1742–1756.PubMedCrossRefGoogle Scholar
  8. Estebanez-Perpina E, Moore JMR, Mar E, Delgado-Rodrigues E, Nguyen P, Baxter JD, Buehrer BM, Webb P, Fletterick RJ, Guy RK. (2005) The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor. J Biol Chem 280:8060–8068.PubMedCrossRefGoogle Scholar
  9. Greschik H, Moras D. (2003) Structure–activity relationship of nuclear receptor-ligand interactions. Curr Top Med Chem 3:1573–1599.PubMedCrossRefGoogle Scholar
  10. He B, Wilson EM. (2003) Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs. Mol Cell Biol 23:2135–2150.PubMedCrossRefGoogle Scholar
  11. He B, Kemppainen JA, Wilson EM. (2000) FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. J Biol Chem 275:22986–22994.PubMedCrossRefGoogle Scholar
  12. He B, Minges JT, Lee LW, Wilson EM. (2002) The FXXLF motif mediates androgen receptorspecific interactions with coregulators. J Biol Chem 277:10226–10235.PubMedCrossRefGoogle Scholar
  13. He B, Gampe RT, Kole AJ, Hnat AT, Stanley TB, An G, Stewart EL, Kalman RI, Minges JT, Wilson EM. (2004) Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16:425–438.PubMedCrossRefGoogle Scholar
  14. Heemers HV, Tindall DJ. (2007) Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28:778–808.PubMedCrossRefGoogle Scholar
  15. Heinlein CA, Chang C. (2002) Androgen receptor coregulators: an overview. Endocr Rev 23:175–200.PubMedCrossRefGoogle Scholar
  16. Hsu C-L, Chen Y-L, Yeh S, Ting H-J, Hu Y-C, Lin H, Wang X, Chang C. (2003) The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL (F?W) and FxxLY new signature motifs. J Biol Chem 278:23691–23698.PubMedCrossRefGoogle Scholar
  17. Hu YC, Yan S, Yeh SD, Sampson ER, Huang J, Li P, Hsu CL, Ting HJ, Lin HK, Wang L, Kim E, Ni J, Chang C. (2004) Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. J Biol Chem 279:33438–33446.PubMedCrossRefGoogle Scholar
  18. Hur E, Pfaff SJ, Payne ES, Gron H, Buehrer BM, Fletterick RJ. (2004) Recognition and accommodation at the androgen receptor coactivator binding interface. PLoS Biol 2:1301–1312.CrossRefGoogle Scholar
  19. Li Y, Lambert MH, Xu HE. (2003) Activation of nuclear receptors: a perspective from functional genomics. Structure 11:741–746.PubMedCrossRefGoogle Scholar
  20. McKenna NJ, O’Malley BW. (2002) Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465–474.PubMedCrossRefGoogle Scholar
  21. Ozers MSS, Marks BD, Gowda K, Kupcho KR, Ervin KM, De Rosier T, Qadir N, Eliason HC, Riddle SM, Shekhani MS. (2007) The androgen receptor T877A mutant recruits LXXLL and FXXLF peptides differently than wild-type androgen receptor in a time-resolved fluorescence resonance energy transfer assay. Biochemistry 46:683–695.PubMedCrossRefGoogle Scholar
  22. Rosenfeld MG, Lunyak VV, Glass CK. (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428.PubMedCrossRefGoogle Scholar
  23. Schaufele F, Carbonell X, Guerbadot M, Borngraeber S, Chapman MS, Ma AAK, Miner JN, Diamond MI. (2005) The structural basis of androgen receptor activation: intramolecular and intermolecular amino–carboxy interactions. Proc Natl Acad Sci USA 102:9802–9807.PubMedCrossRefGoogle Scholar
  24. Steketee K, Berrevoets CA, Dubbink HJ, Doesburg P, Hersmus R, Brinkmann AO, Trapman J. (2002) Amino acids 3-13 and amino acids in and flanking the FXXLF motif modulate the interaction between the amino-terminal and ligand-binding domain of the androgen receptor. Eur J Biochem 269:5780–5791.PubMedCrossRefGoogle Scholar
  25. van de Wijngaart DJ, van Royen ME, Hersmus R, Pike ACW, Houtsmuller AB, Jenster G, Trapman J, Dubbink HJ. (2006) Novel FXXFF and FXXMF motifs in androgen receptor cofactors mediate high affinity and specific interactions with the ligand-binding domain. J Biol Chem 281:19407–19416.PubMedCrossRefGoogle Scholar
  26. van Royen ME, Cunha SM, Brink M, Mattern KA, Nigg AL, Dubbink HJ, Verschure PJ, Trapman J, Houtsmuller AB. (2007) Compartmentalization of androgen receptor protein–protein interactions in living cells. J Cell Biol 177:63–72.PubMedCrossRefGoogle Scholar
  27. Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C. (2004) Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. Mol Cell Biol 24:2202–2213.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of PathologyJosephine Nefkens Institute, Erasmus Medical CenterRotterdamThe Netherlands

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