Phospho-ERα: structure, function, and intervention

The estrogen receptor's intrinsically disordered N-terminal transactivation domain (NTD/AF1) represents a promising yet underexplored therapeutic target in breast cancer. While direct inhibitors for disordered regions in related transcription factors (p53, androgen receptor) have been developed, parallel advances for ER-NTD have been limited by insufficient structural understanding.

In our recent breakthrough (Nature 2025), we elucidated the disorder-function relationship of ER-AF1, focusing on the critical Ser118 phosphorylation site. By integrating small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we discovered that Ser118 phosphorylation triggers an unexpected expansion of the disordered domain while disrupting specific hydrophobic clustering between two aromatic-rich regions. Read more from CWRU’s “The Daily” piece.

This conformational change—driven primarily by hydrophobic rather than electrostatic interactions—proves functionally significant. Mutations mimicking this disruption successfully rescue ER transcriptional activity, target-gene expression, and cell growth that are otherwise impaired by phosphorylation-deficient mutations. This fundamental sequence-structure-function relationship challenges conventional models of disordered proteins and provides essential mechanistic insights for developing targeted breast cancer therapeutics.