Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets

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Model Identifier
BIOMD0000000574
Short description
Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets

This model is described in the article:

Lai M, Brun D, Edelstein SJ, Le Novère N.
PLoS Comput. Biol. 2015 Jan; 11(1): e1004063

Abstract:

Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe) joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins. Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines) several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulin's saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be explained as modulation of a pre-existing dynamic equilibrium between different conformations of calmodulin's lobes, in agreement with linkage theory and MWC-type models.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions.
  • Lai M, Brun D, Edelstein SJ, Le Novère N
  • PLoS computational biology , 1/ 2015 , Volume 11 , pages: e1004063 , PubMed ID: 25611683
  • Babraham Institute, Cambridge, United Kingdom.
  • Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe) joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins. Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines) several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulin's saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be explained as modulation of a pre-existing dynamic equilibrium between different conformations of calmodulin's lobes, in agreement with linkage theory and MWC-type models.
Contributors
Massimo Lai, administrator

Metadata information


Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000574_url.xml SBML L2V4 representation of Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets 1.24 MB Preview | Download

Additional files

BIOMD0000000574-biopax3.owl Auto-generated BioPAX (Level 3) 1.85 MB Preview | Download
BIOMD0000000574.vcml Auto-generated VCML file 1023.64 KB Preview | Download
BIOMD0000000574-biopax2.owl Auto-generated BioPAX (Level 2) 1.05 MB Preview | Download
BIOMD0000000574.png Auto-generated Reaction graph (PNG) 4.23 KB Preview | Download
BIOMD0000000574.xpp Auto-generated XPP file 168.61 KB Preview | Download
MODEL1405060000_CaMKIIeffect.cps Copasi file with the simulation settings to reproduce the above figure is available for download. 1.83 MB Preview | Download
BIOMD0000000574.pdf Auto-generated PDF file 4.58 MB Preview | Download
BIOMD0000000574.svg Auto-generated Reaction graph (SVG) 855.00 bytes Preview | Download
BIOMD0000000574.sci Auto-generated Scilab file 153.64 KB Preview | Download
BIOMD0000000574_urn.xml Auto-generated SBML file with URNs 1.23 MB Preview | Download
BIOMD0000000574.m Auto-generated Octave file 245.23 KB Preview | Download

  • Model originally submitted by : Massimo Lai
  • Submitted: 06-May-2014 13:20:09
  • Last Modified: 21-Dec-2018 18:12:51
Revisions
  • Version: 3 public model Download this version
    • Submitted on: 21-Dec-2018 18:12:51
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: MODEL1405060000_CaMKIIeffect.cps
  • Version: 2 public model Download this version
    • Submitted on: 20-May-2016 19:05:56
    • Submitted by: Massimo Lai
    • With comment: Current version of Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets
  • Version: 1 public model Download this version
    • Submitted on: 06-May-2014 13:20:09
    • Submitted by: Massimo Lai
    • With comment: Original import of Lai2014_calmodulin_hemiconcerted_MWC
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
cam RR ACD rbp

Calmodulin
0.0 mol
cam RR ACD tbp

Neurogranin ; Calmodulin
0.0 mol
cam RR BCD 0

Calmodulin
0.0 mol
cam RT 0 0

Calmodulin
0.0 mol
Reactions
Reactions Rate Parameters
(rbp + cam_RR_ACD_0) => (cam_RR_ACD_rbp)

([rbp] + [Calmodulin]) => ([Calmodulin])
cytosol*(kon_rbp*rbp*cam_RR_ACD_0-koff_rbp_RR*cam_RR_ACD_rbp)

cytosol*(kon_rbp*[rbp]*[Calmodulin]-koff_rbp_RR*[Calmodulin])
koff_rbp_RR = 0.005; kon_rbp = 1.0E8
(ca + cam_RT_0_0) => (cam_RT_B_0)

([calcium(2+)] + [Calmodulin]) => ([Calmodulin])
cytosol*(kon_BR*ca*cam_RT_0_0-koff_BR*cam_RT_B_0)

cytosol*(kon_BR*[calcium(2+)]*[Calmodulin]-koff_BR*[Calmodulin])
koff_BR = 19.7628; kon_BR = 1.0E9
(tbp + cam_RT_0_0) => (cam_RT_0_tbp)

([Neurogranin] + [Calmodulin]) => ([Neurogranin; Calmodulin])
cytosol*(kon_tbp*tbp*cam_RT_0_0-koff_tbp_RT*cam_RT_0_tbp)

cytosol*(kon_tbp*[Neurogranin]*[Calmodulin]-koff_tbp_RT*[Neurogranin; Calmodulin])
koff_tbp_RT = 1.0E8; kon_tbp = 1.0E8
(ca + cam_RR_ACD_tbp) => (cam_RR_ABCD_tbp)

([calcium(2+)] + [Neurogranin; Calmodulin]) => ([Neurogranin; Calmodulin])
cytosol*(kon_BR*ca*cam_RR_ACD_tbp-koff_BR*cam_RR_ABCD_tbp)

cytosol*(kon_BR*[calcium(2+)]*[Neurogranin; Calmodulin]-koff_BR*[Neurogranin; Calmodulin])
koff_BR = 19.7628; kon_BR = 1.0E9
Curator's comment:
(added: 10 Apr 2015, 15:37:03, updated: 10 Apr 2015, 15:37:03)
The full model (two submodels that correspond to each Calmodulin lobe are put together) intact calmodulin with targets: The effect of CaMKII (rbp) bound to Calmodulin (blue plot) in Figure 9 of the reference publication has been reproduced here. Figure 9 in the paper refer only to the C-terminal lobe of calmodulin, whereas the model submitted here is a full model. So, to obtain figure 9 of the paper the following changes are to be made. Effect of CaMKII (rbp) binding to Calmodulin (blue line): Set concentration of CaM to 40µM (4e-05) and that of CaMKII to 100µM (1e-04) Set Kd_rbp_RR = Kd_rbp_TR = 0.95 µM (Same affinity for RR and TR = we don't care about the state of the N-lobe) Set Kd_rbp_RT = Kd_rbp_TT = 88 µM Set Kd_tbp_TT = Kd_tbp_RT = 43 nM Set Kd_tbp_RR = Kd_tbp_TR = 1.05 µM Further, to plot the effect of neurogranin (tbp) binding to Calmodulin (red line in figure 9 of the paper): set CaMKII to 0 and Neurogranin (tbp) to 40 µM (4e-05). to plot the effect of competing targets (purple line in the figure 9 of the paper): set CaMKII to 100µM (1e-04) and Neurogranin (tbp) to 40 µM (4e-05).