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Cooperative binding mitigates the high-dose hook effect.

Ranjita Dutta Roy1,2, Christian Rosenmund2, Melanie I Stefan3,4,5

  • 1Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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|August 16, 2017
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Summary
This summary is machine-generated.

Allosteric regulation mitigates the high-dose hook effect, a phenomenon where increasing protein concentration can decrease complex formation. This study reveals how allostery protects against this effect, with implications for protein activity modulation in vivo.

Keywords:
AllosteryCalmodulinCooperativityHigh-dose Hook effectMechanistic modelProzone effect

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Area of Science:

  • Biochemistry
  • Systems Biology
  • Neuroscience

Background:

  • The high-dose hook effect (prozone effect) describes a decrease in complex formation at high concentrations of a linker protein.
  • Allosterically regulated proteins appear less susceptible to the hook effect.
  • Calmodulin is a calcium-sensing protein crucial for neuronal plasticity.

Purpose of the Study:

  • To mathematically investigate how allostery mitigates the prozone effect.
  • To explore the consequences of allostery and the hook effect using calmodulin as a model.

Main Methods:

  • Combinatorial modeling of a perfect linker protein to describe the hook effect.
  • Kinetic simulations of calmodulin's behavior under allosteric conditions.

Main Results:

  • Allosteric regulation was mathematically shown to mitigate the high-dose hook effect.
  • Calmodulin exhibits a hook effect, which is amplified by the allosteric activator Ca2+/CaMKII.
  • Increased allosteric activator concentration can paradoxically decrease protein activity.

Conclusions:

  • Cooperative binding acts as a protective mechanism against the hook effect.
  • Allosteric modulation of protein cooperativity can lead to counterintuitive effects on protein activity.
  • Findings have implications for understanding in vivo protein regulation by allosteric activators and inhibitors.