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Mechanism of specificity in the Fos-Jun oncoprotein heterodimer

E K O'Shea1, R Rutkowski, P S Kim

  • 1Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.

Cell
|February 21, 1992
PubMed

Insights

Fos and Jun proteins form heterodimers crucial for gene regulation. Specific amino acid sequences and acidic residues drive this preferential binding, impacting transcription.

Area of Science:

  • Molecular Biology
  • Protein-DNA Interactions
  • Gene Regulation

Background:

  • Fos and Jun proteins are products of nuclear proto-oncogenes c-fos and c-jun.
  • They form heterodimers that bind DNA and modulate gene transcription in response to mitogenic stimuli.
  • Leucine zipper regions in Fos and Jun mediate preferential heterodimer formation and fold autonomously as coiled coils.

Purpose of the Study:

  • To identify the minimal amino acid sequences sufficient for preferential Fos-Jun heterodimer formation.
  • To investigate the thermodynamic driving forces behind preferential heterodimerization.

Main Methods:

  • Utilized the GCN4 leucine zipper as a background sequence.
  • Employed pH titration and amino acid replacement strategies to analyze protein interactions.
  • Assessed the role of specific amino acid residues in heterodimer stability.

Main Results:

  • Identified an 8-amino acid sequence from both Fos and Jun sufficient for preferential heterodimer formation.
  • Demonstrated that destabilization of the Fos homodimer by acidic residues is a key thermodynamic driver for preferential heterodimerization.

Conclusions:

  • Specific short amino acid segments within Fos and Jun are sufficient to direct heterodimer formation.
  • Acidic residues play a critical role in the thermodynamics of Fos-Jun heterodimerization, favoring it over homodimerization.

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