Cargando…
Cooperative binding mitigates the high-dose hook effect
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....
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556679/ https://www.ncbi.nlm.nih.gov/pubmed/28807050 http://dx.doi.org/10.1186/s12918-017-0447-8 |
_version_ | 1783257112860688384 |
---|---|
author | Roy, Ranjita Dutta Rosenmund, Christian Stefan, Melanie I. |
author_facet | Roy, Ranjita Dutta Rosenmund, Christian Stefan, Melanie I. |
author_sort | Roy, Ranjita Dutta |
collection | PubMed |
description | 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 Ca (2+)/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 amounts 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-017-0447-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5556679 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-55566792017-08-16 Cooperative binding mitigates the high-dose hook effect Roy, Ranjita Dutta Rosenmund, Christian Stefan, Melanie I. BMC Syst Biol Research Article 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 Ca (2+)/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 amounts 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-017-0447-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-14 /pmc/articles/PMC5556679/ /pubmed/28807050 http://dx.doi.org/10.1186/s12918-017-0447-8 Text en © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Roy, Ranjita Dutta Rosenmund, Christian Stefan, Melanie I. Cooperative binding mitigates the high-dose hook effect |
title | Cooperative binding mitigates the high-dose hook effect |
title_full | Cooperative binding mitigates the high-dose hook effect |
title_fullStr | Cooperative binding mitigates the high-dose hook effect |
title_full_unstemmed | Cooperative binding mitigates the high-dose hook effect |
title_short | Cooperative binding mitigates the high-dose hook effect |
title_sort | cooperative binding mitigates the high-dose hook effect |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556679/ https://www.ncbi.nlm.nih.gov/pubmed/28807050 http://dx.doi.org/10.1186/s12918-017-0447-8 |
work_keys_str_mv | AT royranjitadutta cooperativebindingmitigatesthehighdosehookeffect AT rosenmundchristian cooperativebindingmitigatesthehighdosehookeffect AT stefanmelaniei cooperativebindingmitigatesthehighdosehookeffect |