Effects of sequestration on signal transduction cascades

Authors

  • Nils Blüthgen,

    1. Institute for Theoretical Biology, Humboldt University Berlin, Germany
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    • Present address
      Molecular Neurobiology, Institute of Biology, Free University of Berlin, Germany.

  • Frank J. Bruggeman,

    1. Department of Molecular Cell Physiology, Institute of Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, the Netherlands
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  • Stefan Legewie,

    1. Institute for Theoretical Biology, Humboldt University Berlin, Germany
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  • Hanspeter Herzel,

    1. Institute for Theoretical Biology, Humboldt University Berlin, Germany
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  • Hans V. Westerhoff,

    1. Department of Molecular Cell Physiology, Institute of Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, the Netherlands
    2. Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, School of Chemistry, University of Manchester, UK
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  • Boris N. Kholodenko

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA
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  • Note
    Nils Blüthgen and Frank J. Bruggerman contributed equally to this study.

N. Blüthgen, Institute for Theoretical Biology, Humboldt University Berlin, Invalidenstr. 43, 10115 Berlin, Germany
Fax: +49 30 838 56943
Tel: +49 30 838 56971
E-mail: nils@itb.biologie.hu-berlin.de

Abstract

The building blocks of most signal transduction pathways are pairs of enzymes, such as kinases and phosphatases, that control the activity of protein targets by covalent modification. It has previously been shown [Goldbeter A & Koshland DE (1981) Proc Natl Acad Sci USA78, 6840–6844] that these systems can be highly sensitive to changes in stimuli if their catalysing enzymes are saturated with their target protein substrates. This mechanism, termed zero-order ultrasensitivity, may set thresholds that filter out subthreshold stimuli. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations. Under these conditions a large fraction of the target protein may be sequestrated by the enzymes. This causes a reduction in ultrasensitivity so that the proposed mechanism is unlikely to account for ultrasensitivity under the conditions present in most in vivo signalling cascades. Furthermore, we show that sequestration changes the dynamics of a covalent modification cycle and may account for signal termination and a sign-sensitive delay. Finally, we analyse the effect of sequestration on the dynamics of a complex signal transduction cascade: the mitogen-activated protein kinase (MAPK) cascade with negative feedback. We show that sequestration limits ultrasensitivity in this cascade and may thereby abolish the potential for oscillations induced by negative feedback.

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