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bioRxiv · 10.1101/2023.07.14.548966

Phosphorylation modulates estrogen receptor disorder by altering long-range hydrophobic interactions

Du, Z.·Wang, H.·Wu, C.·Buck, M.·Zheng, W.·Hansen, A. L.·Kao, H.-Y.·Yang, S.
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Abstract

Protein intrinsic disorder is coupled to a range of biological phenomena, from gene regulation to cancer progression. Phosphorylation of the estrogen receptor (ER) at Ser118 through its disordered N-terminal domain (NTD) activates its transcriptional function, but it is challenging to rationalize how this modification regulates ER activity. Using biophysical approaches of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy, we demonstrate that Ser118 phosphorylation triggers long-range conformational changes in ER-NTD, particularly between two hydrophobic clusters of residual structures. Alanine substitution of hydrophobic amino acids near Ser118 produces similar conformational alterations and rescues impaired ER activity caused by a phosphorylation-deficient mutant. These findings establish a direct link between phosphorylation-induced conformational changes and the activation function of this disordered protein as a promising avenue to block ER transcriptional activation.

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Du, Z., Wang, H., Wu, C., Buck, M., Zheng, W., Hansen, A. L., Kao, H.-Y., Yang, S.. 2023-07-15. Phosphorylation modulates estrogen receptor disorder by altering long-range hydrophobic interactions. https://doi.org/10.1101/2023.07.14.548966

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