Androgen-induced NH2- and COOH-terminal interaction inhibits p160 coactivator recruitment by activation function 2

The androgen receptor undergoes an androgen-specific NH2- and COOH-terminal interaction between NH2- terminal motif FXXLF and activation function 2 in the ligand binding domain. We demonstrated previously that activation func tion 2 forms overlapping binding sites for the androgen receptor FXXLF moti f and the LXXLL motifs of p160 coactivators. Here we investigate the influe nce of the NH2- and COOH-terminal interaction on androgen receptor function . Specificity and relative potency of the motif interactions were evaluated by ligand dissociation rate and the stability of chimeras of transcription al intermediary factor 2 with full-length and truncated androgen or glucoco rticoid receptor. The results indicate that the androgen receptor activatio n function 2 interacts specifically and with greater avidity with the singl e FXXLF motif than with the LXXLL motif region of p160 coactivators, wherea s this region of the glucocorticoid receptor interacts preferentially with the LXXLL motifs. Expression of the LXXLL motifs as a fusion protein with t he glucocorticoid receptor resulted in loss of agonist-induced receptor des tabilization and increased half-time of ligand dissociation. The NH2- and C OOH-terminal interaction inhibited binding and activation by transcriptiona l intermediary factor 2. We conclude that the androgen receptor NH2- and CO OH-terminal interaction reduces the dissociation rate of bound androgen, st abilizes the receptor, and inhibits p160 coactivator recruitment by activat ion function 2.