Mutations Targeted to a Predicted Helix in the Extreme Carboxyl-terminal Region of the Human Estrogen Receptor-α Alter Its Response to Estradiol and 4-Hydroxytamoxifen
Year: 2002
Type: article
Abstract: The human estrogen receptor-alpha, a member of the nuclear receptor superfamily, is a ligand-regulated transcriptional modulator. Because comparatively little is known about the extreme carboxyl-terminal region of the estrogen receptor (F domain), we used secondary structure prediction to design mutations that delete the F domain (S554stop), disrupt a possible turn (G556L/G557L), and alter a predicted helix (S559A/E562A, Q565P), and we evaluated the effects of these mutations on hormone binding and transcription activation in response to estradiol and the mixed agonist/antagonist 4-hydroxytamoxifen. Mutations that deleted the F domain (S554stop) or targeted the predicted helix (S559A/E562A, Q565P) greatly reduced or eliminated the agonist activity of 4-hydroxytamoxifen. Deleting the F domain increased the affinity of the receptor for estradiol and decreased the antagonist activity of 4-hydroxytamoxifen. The Q565P mutant exhibited a non-cooperative hormone-binding mechanism, as well as an impaired response to estradiol and increased antagonist activity of 4-hydroxytamoxifen. Our results show that mutations in the F domain alter not only the response to estradiol, the affinity for hormone, and the interaction between receptor subunits but can uncouple the agonist and antagonist activities of 4-hydroxytamoxifen. These results suggest that the F domain modulates the activity of the estrogen receptor-alpha by multiple mechanisms.
Source: Journal of Biological Chemistry
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2076569395