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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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The sequence-structure-function relationship of intrinsic ERα disorder.

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Phosphorylation of oestrogen receptor (ERα) at serine 118 causes its disordered domain to expand, disrupting hydrophobic interactions. This finding offers new insights into ERα function and breast cancer treatment.

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Oestrogen receptor alpha (ERα) is a key driver of breast cancer, often activated by phosphorylation at serine 118.
  • The mechanism of this phosphorylation-induced ERα activation, enabling oestrogen-independent function, remains poorly understood.
  • Understanding this mechanism is critical given ongoing clinical trials targeting this region with kinase inhibitors.

Purpose of the Study:

  • To elucidate the molecular mechanism by which serine 118 phosphorylation affects the intrinsically disordered N-terminal domain of ERα.
  • To investigate the structural and functional consequences of this phosphorylation event.
  • To provide mechanistic insights into intrinsically disordered proteins and nuclear receptor function.

Main Methods:

  • Integration of small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy.
  • Functional studies, including mutational analysis (S118A mutation).
  • Assays for ER transcriptional activity, target-gene expression, and cell growth.

Main Results:

  • Serine 118 phosphorylation induces an unexpected expansion of the ERα disordered N-terminal domain.
  • This expansion disrupts specific hydrophobic clustering between two aromatic-rich regions within the domain.
  • Mutations mimicking this disruption rescue transcriptional activity, gene expression, and cell growth impaired by the S118A mutation.

Conclusions:

  • ERα function is regulated by phosphorylation-induced structural changes in its disordered domain, driven by hydrophobic interactions.
  • These findings challenge purely electrostatic models and offer fundamental insights into intrinsically disordered protein regulation.
  • This work advances the understanding of ERα disorder, crucial for developing targeted breast cancer therapeutics.