Structural studies of mutant glucocorticoid receptor transactivation domains establish a link between transactivation activity in vivo and alpha-helix-forming potential in vitro

We have previously shown, using circular dichroism spectroscopy, that the tau l core peptide has alpha-helix-forming potential in vitro [Dahlman-Wright et al. (1995) Proc. Natl. Acad Sci. U.S.A. 92; 1699-1703]. The tau l core peptide is a 58-amino acid peptide, constituting the core of the transactivation activity of the tau l major transactivation domain of the human glucocorticoid receptor [Dahlman-Wright et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 1619-1623]. Further structural studies of the peptide, using NMR spectroscopy, identified three segments with alpha-helical character. In this report we show that reduced protein expression or stability is not responsible for the reduced in vivo transactivation potential of tau l core peptides with proline substitutions in proposed alpha-helical regions. Rather, the reduced alpha-helix propensity of the corresponding purified peptides in vitro suggests that alpha-helices are involved in the molecular mechanism of glucocorticoid receptor mediated changes in gene activity.