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Cooperative Binding Mitigates the High-Dose Hook Effect

Ranjita Dutta Roy, Christian Rosenmund, Melanie I Stefan
doi: https://doi.org/10.1101/021717
Ranjita Dutta Roy
1Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
2NWFZ, Charité Crossover, Charite Universitätsmedizin, Berlin, Germany.
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Christian Rosenmund
2NWFZ, Charité Crossover, Charite Universitätsmedizin, Berlin, Germany.
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Melanie I Stefan
3Department of Neurobiology, Harvard Medical School, Boston, United States.
4Babraham Institute, Cambridge, United Kingdom.
5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
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  • For correspondence: melanie.stefan@exseed.ed.ac.uk
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Abstract

Background The high-dose hook effect (also called prozone effect) refers to the observation that if a multivalent protein acts as a linker between two parts of a protein complex, then increasing the amount of linker protein in the mixture does not always increase the amount of fully formed complex. On the contrary, at a high enough concentration range the amount of fully formed complex actually decreases. It has been observed that allosterically regulated proteins seem less susceptible to this effect. The aim of this study was two-fold: First, to investigate the mathematical basis of how allostery mitigates the prozone effect. And second, to explore the consequences of allostery and the high-dose hook effect using the example of calmodulin, a calcium-sensing protein that regulates the switch between long-term potentiation and long-term depression in neurons.

Results We use a combinatorial model of a “perfect linker protein” (with infinite binding affinity) to mathematically describe the hook effect and its behaviour under allosteric conditions. We show that allosteric regulation does indeed mitigate the high-dose hook effect. We then turn to calmodulin as a real-life example of an allosteric protein. Using kinetic simulations, we show that calmodulin is indeed subject to a hook effect. We also show that this effect is stronger in the presence of the allosteric activator Ca2+/calmodulin-dependent kinase II (CaMKII), because it reduces the overall cooperativity of the calcium-calmodulin system. It follows that, surprisingly, there are conditions where increased amount of allosteric activator actually decrease the activity of a protein.

Conclusions We show that cooperative binding can indeed act as a protective mechanism against the hook effect. This will have implications in vivo where the extent of cooperativity of a protein can be modulated, for instance, by allosteric activators or inhibitors. This can result in counterintuitive effects of decreased activity with increased concentrations of both the allosteric protein itself and its allosteric activators.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 12, 2017.
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Cooperative Binding Mitigates the High-Dose Hook Effect
Ranjita Dutta Roy, Christian Rosenmund, Melanie I Stefan
bioRxiv 021717; doi: https://doi.org/10.1101/021717
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Cooperative Binding Mitigates the High-Dose Hook Effect
Ranjita Dutta Roy, Christian Rosenmund, Melanie I Stefan
bioRxiv 021717; doi: https://doi.org/10.1101/021717

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