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Related Experiment Videos

S-palmitoylation modulates human estrogen receptor-alpha functions.

Filippo Acconcia1, Paolo Ascenzi, Giulia Fabozzi

  • 1Department of Biology, University Roma Tre, Viale G. Marconi, 446, I-00146, Rome, Italy.

Biochemical and Biophysical Research Communications
|March 23, 2004
PubMed
Summary

S-palmitoylation of estrogen receptor-alpha (ERalpha) at Cys447 is crucial for its plasma membrane localization and rapid E2-induced functions, like ERK activation. This modification is key for non-genomic signaling pathways.

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Area of Science:

  • Molecular Endocrinology
  • Cell Biology
  • Biochemistry

Background:

  • Rapid, non-genomic functions of 17beta-estradiol (E2) are mediated by estrogen receptor-alpha (ERalpha) at the plasma membrane.
  • S-palmitoylation, a lipid modification, is a potential mechanism for ERalpha's membrane association.

Purpose of the Study:

  • To investigate the role of S-palmitoylation at Cys447 of ERalpha in its plasma membrane localization and E2-induced rapid signaling.
  • To elucidate the mechanism by which ERalpha mediates rapid, non-genomic E2 functions.

Main Methods:

  • Site-directed mutagenesis of ERalpha at Cys447 to Alanine (Cys447Ala).
  • Transfection of wild-type and mutant ERalpha into ER-devoid HeLa cells.
  • Assessment of ERalpha palmitoylation using [(3)H]palmitate.

Related Experiment Videos

  • Measurement of E2-induced extracellular regulated kinase (ERK) phosphorylation.
  • Analysis of E2-induced transactivation of an estrogen-responsive element (ERE) reporter construct.
  • Inhibition of palmitoylation using 2-bromo-hexadecanoic acid.

    • Main Results:

    • Mutation of Cys447 to Ala significantly impaired ERalpha palmitoylation.
    • The Cys447Ala mutation abolished E2-induced rapid ERK phosphorylation in HeLa cells.
    • Cys447Ala mutation decreased E2-induced transactivation of an ERE construct.
    • Inhibition of palmitoyl-acyltransferase with 2-bromo-hexadecanoic acid mimicked the effects of the Cys447Ala mutation.
    • Palmitoylation occurred in the presence of the DNA-binding domain but not the ligand-binding domain (E domain).

    Conclusions:

    • Cys447 is essential for ERalpha S-palmitoylation.
    • ERalpha palmitoylation, mediated by Cys447, is critical for E2-induced non-genomic rapid signaling, including ERK activation.
    • The ligand-binding domain (E domain) is involved in ERalpha palmitoylation.