Amino acids 3-13 and amino acids in and flanking the 23FxxLF27 motif modulate the interaction between the N-terminal and ligand-binding domain of the androgen receptor

The N-terminal domain (NTD) and the ligand-binding domain (LBD) of the androgen receptor (AR) exhibit ligand dependent interaction (N/Cinteraction). Amino cids 3-36 in the NTD (AR(3-36)) play dominant role in this interaction. Previously, it has been shown that PhixxPhiPhi motif in AR(3-36), (23)FxxLF(27), is essential for LBD interaction. We demonstrate in the current study that AR(3-36) can be subdivided into two functionally distinct fragments: AR(3-13) and AR(16-36). AR(3-13) does not directly interact with the AR LBD, but rather contributes to the transactivation function of the AR.NTD-AR.LBD complex. AR(16-36), encompassing the (23)FxxLF(27) motif, is predicted to fold into long amphipathic alpha-helix. A second PhixxPhiPhi candidate protein interaction motif within the helical structure, (VREVI34)-V-30, shows no affinity to the LBD. Within AR(16-36), amino acid residues in and flanking the (23)FxxLF(27) motif re demonstrated to modulate N/Cinteraction. Substitution of Q24 and N25 by alanine residues enhances N/Cinteraction. Substitution of amino cids flanking the (23)FxxLF(27) motif by alanines are inhibitory to LBD interaction.