tailieunhanh - Báo cáo Y học: 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 a ligand–dependent interaction (N/Cinteraction). Amino acids 3–36 in theNTD(AR3)36) play a dominant role in this interaction. Previously, it has been shown that a FxxFF motif inAR3)36 , 23 FxxLF 27 , is essential forLBDinteraction. We demonstrate in the current study that AR3)36 can be subdivided into two functionally distinct fragments: AR3)13 andAR16))13does not directly interact with the AR LBD, but rather contributes to the transactivation function of | Eur. J. Biochem. 269 5780-5791 2002 FEBS 2002 doi 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 Karine Steketee1 I Cor A. Berrevoets2 Hendrikus J. Dubbink1 I Paul Doesburg1 Remko Hersmus1 Albert O. Brinkmann2 and Jan Trapman1 1Department of Pathology Josephine Nefkens Institute Erasmus Medical Center Rotterdam the Netherlands department of Reproduction and Development Erasmus Medical Center Rotterdam the Netherlands The N-terminal domain NTD and the ligand-binding domain LBD of the androgen receptor AR exhibit a ligand-dependent interaction N C interaetion . Amino acids 3-36 in the NTD AR3_36 play a dominant role in this interaction. Previously it has been shown that a FxxFF motif in AR3_36 23FxxLF27 is essential for LBD interaction. We demonstrate in the current study that AR3_36 can be subdivided into two functionally distinct fragments AR3_13 and AR16_36. AR3_13 does not directly interact with the AR LBD but rather contributes to the transactivation function of the complex. AR16_36 encompassing the 23FxxLF27 motif is predicted to fold into a long amphipathic a-helix. A second FxxFF candidate protein interaction motif within the helical structure 30VREVI34 shows no affinity to the LBD. Within AR16_36 amino acid residues in and flanking the 23FxxLF27 motif are demonstrated to modulate N C inferaction. íSLibtiítuiKm of Q44 and N25 by alanine residues enhances N C 01 61 1011011. Substitution of amino acids flanking the 23FxxLF27 motif by alanines are inhibitory to LBD interaction. Keywords androgen receptor transcription activation domain ligand-binding domain amphipathic a-helix FxxLF. The androgen receptor AR is a member of the steroid receptor subgroup of the nuclear receptor family of transcription factors. Nuclear receptors have a modular structure composed of a moderately conserved .