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Related Experiment Videos

Optimization of specificity in a cellular protein interaction network by negative selection.

Ali Zarrinpar1, Sang-Hyun Park, Wendell A Lim

  • 1Program in Biological Sciences, University of California, San Francisco, 600 16th Street, San Francisco, California 94143-2240, USA.

Nature
|December 12, 2003
PubMed
Summary

Yeast proteins show high specificity in cellular signaling. The Pbs2 peptide ligand interacts uniquely with the Sho1 SH3 domain, demonstrating optimized specificity within biological networks.

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Area of Science:

  • Molecular Biology
  • Systems Biology
  • Evolutionary Biology

Background:

  • Cellular signaling networks rely on modular protein-interaction domains.
  • Organisms possess multiple versions of these domains, like 27 Src homology 3 (SH3) domains in yeast.
  • Potential for cross-reaction exists due to domain redundancy.

Purpose of the Study:

  • To investigate the specificity of isolated protein-interaction domains.
  • To determine if context is the sole determinant of specificity in signaling networks.
  • To explore the evolutionary optimization of domain-ligand interactions.

Main Methods:

  • In vivo and in vitro assays to test Pbs2 peptide-SH3 domain interactions.
  • Analysis of cross-reactivity with other yeast SH3 domains.

Related Experiment Videos

  • Assessment of fitness defects in Pbs2 motif variants with altered specificity.

    • Main Results:

    • The Pbs2 peptide ligand exhibits near-absolute specificity for the Sho1 SH3 domain within the yeast proteome.
    • No cross-reactivity was observed with other yeast SH3 domains.
    • Non-yeast SH3 domains showed reduced specificity with the Pbs2 peptide, and variants caused fitness defects.

    Conclusions:

    • Isolated domain-ligand pairs can achieve high biological specificity.
    • The Pbs2 motif appears optimized to avoid cross-reactions with yeast-specific SH3 domains.
    • System-wide negative selection drives specificity optimization in complex interaction networks.