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Related Experiment Videos

Multisite protein phosphorylation makes a good threshold but can be a poor switch.

Jeremy Gunawardena1

  • 1Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. jeremy@hms.harvard.edu

Proceedings of the National Academy of Sciences of the United States of America
|October 1, 2005
PubMed
Summary

Multisite protein phosphorylation creates cellular thresholds for signaling regulation. Increasing phosphorylation sites establishes a threshold, but may lead to gradual, not abrupt, switching between signaling states.

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Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Phosphorylation and dephosphorylation are key eukaryotic signaling mechanisms, regulating approximately 30% of proteins.
  • Existing models suggest multiple phosphorylation sites enhance switch-like regulation, a view supported by studies on substrates like cyclin E and Sic1.

Purpose of the Study:

  • To analytically investigate the regulation of multisite phosphorylation.
  • To determine how the number of phosphorylation sites influences the cellular phosphorylation state and signaling.
  • To re-evaluate the relationship between phosphorylation sites and switching efficiency.

Main Methods:

  • Analytical modeling of ordered distributive multisite phosphorylation.
  • Mathematical analysis of kinase and phosphatase activity ratios.

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  • Examination of substrate phosphorylation dynamics.

    • Main Results:

    • Multisite phosphorylation establishes an efficient threshold, maintaining low maximal phosphorylation below a certain kinase/phosphatase activity ratio.
    • This threshold increases with the number of phosphorylation sites (n).
    • Above the threshold, the response can be gradual and hyperbolic with increasing n, rather than abruptly switching.

    Conclusions:

    • The number of phosphorylation sites (n) alone does not guarantee abrupt switching; thresholding is a primary outcome.
    • Conventional measures of ultrasensitivity require modification to distinguish thresholding from switching.
    • Further experimental studies are needed to explore factors influencing switching efficiency in multisite phosphorylation systems.