Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes.
Protein activity is often regulated by ligand binding or by post-translational modifications such as phosphorylation. Moreover, proteins that are regulated in this way often contain multiple ligand binding sites or modification sites, which can operate to create an ultrasensitive dose response. Here...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-08-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1007966 |
| _version_ | 1819029984945111040 |
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| author | Leonila Lagunes Lee Bardwell German A Enciso |
| author_facet | Leonila Lagunes Lee Bardwell German A Enciso |
| author_sort | Leonila Lagunes |
| collection | DOAJ |
| description | Protein activity is often regulated by ligand binding or by post-translational modifications such as phosphorylation. Moreover, proteins that are regulated in this way often contain multiple ligand binding sites or modification sites, which can operate to create an ultrasensitive dose response. Here, we consider the contribution of the individual modification/binding sites to the activation process, and how their individual values affect the ultrasensitive behavior of the overall system. We use a generalized Monod-Wyman-Changeux (MWC) model that allows for variable conformational free energy contributions from distinct sites, and associate a so-called activation parameter to each site. Our analysis shows that the ultrasensitivity generally increases as the conformational free energy contribution from one or more sites is strengthened. Furthermore, ultrasensitivity depends on the mean of the activation parameters and not on their variability. In some cases, we find that the best way to maximize ultrasensitivity is to make the contribution from all sites as strong as possible. These results provide insights into the performance objectives of multiple modification/binding sites and thus help gain a greater understanding of signaling and its role in diseases. |
| first_indexed | 2024-12-21T06:22:57Z |
| format | Article |
| id | doaj.art-fbea63a5a67a4e798e5de024887e67bd |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-12-21T06:22:57Z |
| publishDate | 2020-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-fbea63a5a67a4e798e5de024887e67bd2022-12-21T19:13:13ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582020-08-01168e100796610.1371/journal.pcbi.1007966Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes.Leonila LagunesLee BardwellGerman A EncisoProtein activity is often regulated by ligand binding or by post-translational modifications such as phosphorylation. Moreover, proteins that are regulated in this way often contain multiple ligand binding sites or modification sites, which can operate to create an ultrasensitive dose response. Here, we consider the contribution of the individual modification/binding sites to the activation process, and how their individual values affect the ultrasensitive behavior of the overall system. We use a generalized Monod-Wyman-Changeux (MWC) model that allows for variable conformational free energy contributions from distinct sites, and associate a so-called activation parameter to each site. Our analysis shows that the ultrasensitivity generally increases as the conformational free energy contribution from one or more sites is strengthened. Furthermore, ultrasensitivity depends on the mean of the activation parameters and not on their variability. In some cases, we find that the best way to maximize ultrasensitivity is to make the contribution from all sites as strong as possible. These results provide insights into the performance objectives of multiple modification/binding sites and thus help gain a greater understanding of signaling and its role in diseases.https://doi.org/10.1371/journal.pcbi.1007966 |
| spellingShingle | Leonila Lagunes Lee Bardwell German A Enciso Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes. PLoS Computational Biology |
| title | Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes. |
| title_full | Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes. |
| title_fullStr | Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes. |
| title_full_unstemmed | Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes. |
| title_short | Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes. |
| title_sort | effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes |
| url | https://doi.org/10.1371/journal.pcbi.1007966 |
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