A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation.
Ca2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-12-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1006941 |
| _version_ | 1811176405257420800 |
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| author | Matthew C Pharris Neal M Patel Tyler G VanDyk Thomas M Bartol Terrence J Sejnowski Mary B Kennedy Melanie I Stefan Tamara L Kinzer-Ursem |
| author_facet | Matthew C Pharris Neal M Patel Tyler G VanDyk Thomas M Bartol Terrence J Sejnowski Mary B Kennedy Melanie I Stefan Tamara L Kinzer-Ursem |
| author_sort | Matthew C Pharris |
| collection | DOAJ |
| description | Ca2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme's subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of a twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous experimental measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other's binding to CaMKII. Our results suggest a functional mechanism for the so-called "CaM trapping" phenomenon, wherein Ca2+/CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity. |
| first_indexed | 2024-04-10T19:52:03Z |
| format | Article |
| id | doaj.art-bc96005544cc48cabfc8b0e18f37a222 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-10T19:52:03Z |
| publishDate | 2019-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-bc96005544cc48cabfc8b0e18f37a2222023-01-28T05:30:29ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582019-12-011512e100694110.1371/journal.pcbi.1006941A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation.Matthew C PharrisNeal M PatelTyler G VanDykThomas M BartolTerrence J SejnowskiMary B KennedyMelanie I StefanTamara L Kinzer-UrsemCa2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme's subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of a twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous experimental measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other's binding to CaMKII. Our results suggest a functional mechanism for the so-called "CaM trapping" phenomenon, wherein Ca2+/CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity.https://doi.org/10.1371/journal.pcbi.1006941 |
| spellingShingle | Matthew C Pharris Neal M Patel Tyler G VanDyk Thomas M Bartol Terrence J Sejnowski Mary B Kennedy Melanie I Stefan Tamara L Kinzer-Ursem A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. PLoS Computational Biology |
| title | A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. |
| title_full | A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. |
| title_fullStr | A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. |
| title_full_unstemmed | A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. |
| title_short | A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. |
| title_sort | multi state model of the camkii dodecamer suggests a role for calmodulin in maintenance of autophosphorylation |
| url | https://doi.org/10.1371/journal.pcbi.1006941 |
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