Surveying helix 12 dynamics within constitutively active estrogen receptors using bipartite tetracysteine display.

ABSTRACT: Somatic Y537S and D538G mutations within the estrogen receptor alpha ligand-binding domain (ERα-LBD) have been linked to enhanced cell proliferation, survival, and metastases in ER-positive breast cancers. Such mutations are thought to confer ligand-independent receptor activation by increasing the flexibility of helix 12 (H12), a segment within the ERα-LBD that acts as a dynamic regulator of ERα activity. We employed bipartite tetracysteine display coupled with the biarsenical profluorophore FlAsH-EDT₂ to monitor ligand-independent structural transitions of H12 in ERα-LBDs that include Y537S or D538G mutations. Our results show that in the absence of 17β-estradiol, Y537S and D538G mutations cause H12 to fold into a "stable agonist" conformation that is similar to liganded (17β-

SUBMITTER: Sendanayake LR 

PROVIDER: S-EPMC11889964 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature