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Nicolas Le Novére"Modélisation du comportement des protéines allostériques impliquées dans la plasticité synaptique"

Abstract :


Most common forms of short-term synaptic plasticities are associated with non-linear responses to calcium increases in the post-synaptic compartment.
Cooperativity, a form of ultra-sensitivity where the effect of a signal increases in a non-linear fashion with the intensity of the signal, is often considered as a mean to implement a thresholding function, resulting in a molecular on-off switch. The "cooperative" nature is due to the existence of several non-independent sites responding to the signal. Those sites are often carried by different identical monomers within a symmetrical assembly, and for half a century the emerging cooperative properties have been successfully explained by the concerted model of Monod, Wyman and Changeux. Calmodulin, one of the main calcium sensors in eukaryotic cells, is a small protein that carries four calcium binding sites with different affinities. One can extend the MWC framework to explain the properties of calmodulin, and in particular the apparent increasing calcium affinity with fractional occupancy, the activity of non-saturated forms of calmodulin, and the increase in calcium affinity once calmodulin is bound to a target. Because calmodulin can bind several targets with different affinities, the allosteric model can explain that it can be used to implement changeover switches, where it can modulate different targets at different calcium concentrations. In particular, allosteric properties of calmodulin may suffice to explain the differential activation of calcineurin, leading to synaptic long-term depression, and calcium/calmodulin kinase II, leading to synaptic long term potentiation, a molecular basis of learning and memory.Because the concentration of calmodulin in neurons is of the same order of magnitude than the dissociation constants for calcium, it is subjected to a phenomenon called "ligand depletion". Amplified in cooperative systems, this phenomenon causes the dynamic range and the cooperativity of response to calcium to be different in different neurons. Ligand-depletion also provide a mechanism to quickly fine-tune the dynamic of response to environmental signals.


Invitation de Christophe Mulle

Selected publications

Edelstein S.J., Stefan M.I, Le Novère N. Ligand depletion in vivo modulates the dynamic range of cooperative signal transduction. Submitted.
 
Stefan M.I., Edelstein S.J., Le Novère N. Computing phenomenologic Adair-Klotz constants from microscopic MWC parameters. BMC Sys Biol (2009), 3: 68
 
Stefan M.I., Edelstein S.J., Le Novère N. An allosteric model of calmodulin explains differential activation of PP2B and CaMKII. Proc Natl Acad Sci USA (2008), 105: 10768-10773.