Dataset Information

Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets

ABSTRACT: Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets This model is described in the article: Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions. 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. This model is hosted on BioModels Database and identified by: BIOMD0000000574. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic 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.

SUBMITTER: Massimo Lai

PROVIDER: BIOMD0000000574 | BioModels | 2015-04-10

REPOSITORIES: BioModels

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Publications

Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions.

Lai Massimo M Brun Denis D Edelstein Stuart J SJ Le Novère Nicolas N

PLoS computational biology 20150122 1

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 ...[more]

PMID: 25611683

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Dataset Information

Lai2014 - Hemiconcerted MWC model of intact calmodulin with two targets

Publications

Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions.

Similar Datasets

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