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A Multi-state Model of the CaMKII Holoenzyme using MCell 3.3

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By Matthew C Pharris1, Tamara L Kinzer-Ursem1

Purdue University

This model uses a specialized rule-based syntax in MCell 3.3 to model the twelve-subunit CaMKII holoenzyme without inducing combinatorial explosion. The model allows us to explore the regulation of CaMKII activation and autophosphorylation.

Version 2.0 - published on 29 Jul 2019 doi:10.4231/MV0Z-8Z57 - cite this Archived on 29 Aug 2019

Licensed under CC0 1.0 Universal

TotalCaMKII.jpg

Description

In the hippocampus, the dynamic fluctuation in size and strength of neuronal connections is thought to underlie learning and memory processes. These fluctuations, called synaptic plasticity, are in-part regulated by the protein calcium/calmodulin-dependent kinase II (CaMKII). During synaptic plasticity, CaMKII becomes activated in the presence of calcium ions (Ca2+) and calmodulin (CaM), allowing it to interact enzymatically with downstream binding partners. Interestingly, activated CaMKII can phosphorylate itself, resulting in state changes that allow CaMKII to be functionally active independent of Ca2+/CaM. Phosphorylation of CaMKII at Thr-286/287 has been shown to be a critical component of learning and memory. To explore the molecular mechanisms that regulate the activity of CaMKII holoenzymes, we use a rule-based approach that reduces computational complexity normally associated with representing the wide variety of functional states that a CaMKII holoenzyme can adopt. Using this approach we observe regulatory mechanisms that might be obscured by reductive approaches. Our results newly suggest that CaMKII phosphorylation at Thr-286/287 is stabilized by a mechanism in which CaM structurally excludes phosphatase binding at that site.

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Notes

Version 2 contains additional model code for running the so-called "9-state-1-step" version of the CaMKII dodecamer model, along with Prism files containing the raw data for the key figures of the paper.

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