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A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation

Pharris, Matthew C. and Bartol, Thomas M. and Sejnowski, Terrence J. and Kennedy, Mary B. and Stefan, Melanie I. and Kinzer-Ursem, Tamara L. (2019) A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20190312-144831821

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Abstract

Ca^(2+)/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 twelve 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 the twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca^(2+)/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca^(2+)/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca^(2+)/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, such that Ca^(2+)/CaM structurally excludes phosphatase binding and thereby prolongs CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca^(2+)/CaM may be an important mechanism for regulation of synaptic plasticity.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/575712DOIDiscussion Paper
https://www.biorxiv.org/content/10.1101/575712v1OrganizationDiscussion Paper
https://doi.org/10.4231/MBPK-D277DOIData
ORCID:
AuthorORCID
Sejnowski, Terrence J.0000-0002-0622-7391
Kennedy, Mary B.0000-0003-1369-0525
Additional Information: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 4.0 International license. bioRxiv preprint first posted online Mar. 12, 2019. All MCell code and associated files are available online at Github, the Purdue University Research Repository (DOI: 10.4231/MBPK-D277), and the University of Edinburgh Repository. The authors offer special thanks to Neal Patel for many helpful conversations and assistance creating the CaMKII movie visualizations in CellBlender. We also thank Stefan Mihalas, Nicolas LeNovere, Elizabeth Phillips, Kaisa Ejendal, David Umulis, and Tyler VanDyk for their helpful advice and comments on the manuscript.
Record Number:CaltechAUTHORS:20190312-144831821
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190312-144831821
Official Citation:A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation. Matthew C Pharris, Thomas M. Bartol, Terrence J. Sejnowski, Mary B. Kennedy, Melanie I. Stefan, Tamara L. Kinzer-Ursem bioRxiv 575712; doi: https://doi.org/10.1101/575712
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93743
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Mar 2019 22:02
Last Modified:03 Oct 2019 20:57

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