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

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 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 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, wherein Ca 2+ /CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca 2+ /CaM may be an important mechanism for regulation of synaptic plasticity.

A spatial model of autophosphorylation of Ca2+/calmodulin-dependent protein kinase II in a glutamatergic spine reveals dynamics of kinase activation in the first several seconds after a complex synaptic stimulus

“…However, it did significantly prolong the lifetimes of CaMKII-bound CaM4, CaM2C, and CaM2C1N. In an an earlier modeling study (Pharris et al, 2019), it was noted that the CaM-binding domain on CaMKII overlaps significantly with the region on the CaMKII regulatory domain immediately downstream of T-286, near where PP1 would bind to catalyze dephosphorylation of T-286. Therefore, they suggested that bound CaM might block or partially inhibit reversal by PP1 of CaMKII autophosphorylation.…”

A biochemical description of postsynaptic plasticity—with timescales ranging from milliseconds to seconds

“…It also remains unclear experimentally whether stable E-LTP can be achieved by the biochemical activity of CaMKII and PP. Although many modeling simulations observe and implement steady states of the CaMKII & PP system ( 52 – 55 ), newer findings show that the stable plasticity does not have to rely on the stability of the fully activated state of CaMKII ( 35 , 56 , 57 ). Here, we focus on modeling the induction of early LTP/D, over the first several minutes.…”

“…Most previous models of STDP [and all models of BTSP] are phenomenological descriptions of the strengthening/weakening of synapses, including the STDP work ( 58 , 59 , 60 ) [and the BTSP work ( 61 , 62 )]. Notable exceptions are the works of ( 28 , 57 ), which model in some detail the biochemical reactions of CaMKII. Our model of the biochemistry in the PSD begins from the detailed model of the activation of CaMKII of ( 28 ) but with several enhancements: First, to model the binding and disassociation of molecules and how they influence phosphorylation and dephosphorylation, we replace Michaelis–Menten schemes (quasi-steady-state) with quasi-equilibrium representations, which are a more fundamental description of the catalytic reactions.…”

Data-driven learning how oncogenic gene expression locally alters heterocellular networks

“…For instance, a rule-based model was used to interpret single-molecule detection of multisite phosphorylation on intact EGFR to reveal a new role for the abundance of adapter proteins to redirect signaling 65 . Given the challenges with representing the various activation states of a 12-subunit Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) holoenzyme that is essential for memory function, a rule-based model identified a molecular mechanism stabilizing protein activity that was obscured in prior reduced models 66 . Inspired by engineering better CAR T cells, Rohrs et al developed a rule-based model to interpret site-specific phosphorylation dynamics associated with Chimeric Antigen Receptors 67 .…”