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Calmodulin Transduces Ca2+ Oscillations into Differential Regulation of Its Target Proteins

Slavov, Nikolai ; Carey, Jannette and Linse, Sara LU (2013) In ACS Chemical Neuroscience 4(4). p.601-612
Abstract
Diverse physiological processes are regulated differentially by Ca2+ oscillations through the common regulatory hub calmodulin. The capacity of calmodulin to combine specificity with promiscuity remains to be resolved. Here we propose a mechanism based on the molecular properties of calmodulin, its two domains with separate Ca2+ binding affinities, and target exchange rates that depend on both target identity and Ca2+ occupancy. The binding dynamics among Ca2+ Mg2+, calmodulin, and its targets were modeled with mass-action differential equations based on experimentally determined protein concentrations and rate constants. The model predicts that the activation of calcineurin and nitric oxide synthase depends nonmonotonically on... (More)
Diverse physiological processes are regulated differentially by Ca2+ oscillations through the common regulatory hub calmodulin. The capacity of calmodulin to combine specificity with promiscuity remains to be resolved. Here we propose a mechanism based on the molecular properties of calmodulin, its two domains with separate Ca2+ binding affinities, and target exchange rates that depend on both target identity and Ca2+ occupancy. The binding dynamics among Ca2+ Mg2+, calmodulin, and its targets were modeled with mass-action differential equations based on experimentally determined protein concentrations and rate constants. The model predicts that the activation of calcineurin and nitric oxide synthase depends nonmonotonically on Ca2+-oscillation frequency. Preferential activation reaches a maximum at a target-specific frequency. Differential activation arises from the accumulation of inactive calmodulin-target intermediate complexes between Ca2+ transients. Their accumulation provides the system with hysteresis and favors activation of some targets at the expense of others. The generality of this result was tested by simulating 60 000 networks with two, four, or eight targets with concentrations and rate constants from experimentally determined ranges. Most networks exhibit differential activation that increases in magnitude with the number of targets. Moreover, differential activation increases with decreasing calmodulin concentration due to competition among targets. The results rationalize calmodulin signaling in terms of the network topology and the molecular properties of calmodulin. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Signal transduction, oscillatory dynamics, frequency dependence, ligand, binding, cooperativity, tuning, emergent property
in
ACS Chemical Neuroscience
volume
4
issue
4
pages
601 - 612
publisher
The American Chemical Society (ACS)
external identifiers
  • wos:000317873000010
  • scopus:84876535960
  • pmid:23384199
ISSN
1948-7193
DOI
10.1021/cn300218d
language
English
LU publication?
yes
id
45b7de67-a19b-4543-86de-58fc490417bf (old id 3854759)
date added to LUP
2016-04-01 14:41:47
date last changed
2020-01-12 16:53:03
@article{45b7de67-a19b-4543-86de-58fc490417bf,
  abstract     = {Diverse physiological processes are regulated differentially by Ca2+ oscillations through the common regulatory hub calmodulin. The capacity of calmodulin to combine specificity with promiscuity remains to be resolved. Here we propose a mechanism based on the molecular properties of calmodulin, its two domains with separate Ca2+ binding affinities, and target exchange rates that depend on both target identity and Ca2+ occupancy. The binding dynamics among Ca2+ Mg2+, calmodulin, and its targets were modeled with mass-action differential equations based on experimentally determined protein concentrations and rate constants. The model predicts that the activation of calcineurin and nitric oxide synthase depends nonmonotonically on Ca2+-oscillation frequency. Preferential activation reaches a maximum at a target-specific frequency. Differential activation arises from the accumulation of inactive calmodulin-target intermediate complexes between Ca2+ transients. Their accumulation provides the system with hysteresis and favors activation of some targets at the expense of others. The generality of this result was tested by simulating 60 000 networks with two, four, or eight targets with concentrations and rate constants from experimentally determined ranges. Most networks exhibit differential activation that increases in magnitude with the number of targets. Moreover, differential activation increases with decreasing calmodulin concentration due to competition among targets. The results rationalize calmodulin signaling in terms of the network topology and the molecular properties of calmodulin.},
  author       = {Slavov, Nikolai and Carey, Jannette and Linse, Sara},
  issn         = {1948-7193},
  language     = {eng},
  number       = {4},
  pages        = {601--612},
  publisher    = {The American Chemical Society (ACS)},
  series       = {ACS Chemical Neuroscience},
  title        = {Calmodulin Transduces Ca2+ Oscillations into Differential Regulation of Its Target Proteins},
  url          = {http://dx.doi.org/10.1021/cn300218d},
  doi          = {10.1021/cn300218d},
  volume       = {4},
  year         = {2013},
}