Interaction of the Androgen Receptor Ligand-Binding Domain with the N-Terminal Domain and with Coactivators
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.
KeywordsAmino Acid Residue Androgen Receptor Cyproterone Acetate Peptide Motif Phenylalanine Residue
The author is indebted to Martin van Royen and Dennis van de Wijngaart for help with preparation of the manuscript.
- 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
- 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
- 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
- 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
- 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