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Kinetic regulation of multi-ligand binding proteins.

Salakhieva DV, Sadreev II, Chen MZ, Umezawa Y, Evstifeev AI, Welsh GI, Kotov NV - BMC Syst Biol (2016)

Bottom Line: Therefore, buffering effects significantly influence the amounts of free ligands.The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands.Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites.

View Article: PubMed Central - PubMed

Affiliation: Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008, Kazan, Russia.

ABSTRACT

Background: Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation.

Results: In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated.

Conclusions: The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion.

No MeSH data available.


Related in: MedlinePlus

The effect of the number of binding sites on intermediate conformations. The maximum magnitude of protein conformations in complex with one, two and three ligand molecules are shown as a function of the total number of binding sites. The relative amount of ligand binding by conformations bound to a specific number of sites clearly diminishes as the number of sites grow
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Fig1: The effect of the number of binding sites on intermediate conformations. The maximum magnitude of protein conformations in complex with one, two and three ligand molecules are shown as a function of the total number of binding sites. The relative amount of ligand binding by conformations bound to a specific number of sites clearly diminishes as the number of sites grow

Mentions: Figure 1 shows the maximum protein conformations in complex with one, two and three ligands as a function of the number of binding sites (Eq. (14) in Methods). The graph demonstrates that the magnitude of the ligand-multisite complexes decreases dramatically as the number of binding sites increases. The presented results suggest that the relative magnitude of individual intermediate conformations decreases as the number of binding sites increases. This in turn results in subtler regulatory effects of those proteins with larger number of ligand binding sites. For example, in CaM that has four binding sites for calcium [18], the presence of four sites leads to the increased multifunctionality of this protein due to the additional regulatory properties of intermediate conformations [24]. However, as an exception some forms of CaM have six binding sites [44, 45]. In this case, according to Fig. 1 the magnitude of intermediate conformations significantly decreases compared to the case of four binding sites, resulting in decreased regulatory properties of the protein. The presence of more than one binding site results in increased multifunctionality of the protein but at the same time leads the decrease of the regulatory effects. Thus, it seems that there is an “optimal” number of binding sites, which have been developed during the evolution, for instance four calcium binding sites in CaM.Fig. 1


Kinetic regulation of multi-ligand binding proteins.

Salakhieva DV, Sadreev II, Chen MZ, Umezawa Y, Evstifeev AI, Welsh GI, Kotov NV - BMC Syst Biol (2016)

The effect of the number of binding sites on intermediate conformations. The maximum magnitude of protein conformations in complex with one, two and three ligand molecules are shown as a function of the total number of binding sites. The relative amount of ligand binding by conformations bound to a specific number of sites clearly diminishes as the number of sites grow
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835871&req=5

Fig1: The effect of the number of binding sites on intermediate conformations. The maximum magnitude of protein conformations in complex with one, two and three ligand molecules are shown as a function of the total number of binding sites. The relative amount of ligand binding by conformations bound to a specific number of sites clearly diminishes as the number of sites grow
Mentions: Figure 1 shows the maximum protein conformations in complex with one, two and three ligands as a function of the number of binding sites (Eq. (14) in Methods). The graph demonstrates that the magnitude of the ligand-multisite complexes decreases dramatically as the number of binding sites increases. The presented results suggest that the relative magnitude of individual intermediate conformations decreases as the number of binding sites increases. This in turn results in subtler regulatory effects of those proteins with larger number of ligand binding sites. For example, in CaM that has four binding sites for calcium [18], the presence of four sites leads to the increased multifunctionality of this protein due to the additional regulatory properties of intermediate conformations [24]. However, as an exception some forms of CaM have six binding sites [44, 45]. In this case, according to Fig. 1 the magnitude of intermediate conformations significantly decreases compared to the case of four binding sites, resulting in decreased regulatory properties of the protein. The presence of more than one binding site results in increased multifunctionality of the protein but at the same time leads the decrease of the regulatory effects. Thus, it seems that there is an “optimal” number of binding sites, which have been developed during the evolution, for instance four calcium binding sites in CaM.Fig. 1

Bottom Line: Therefore, buffering effects significantly influence the amounts of free ligands.The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands.Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites.

View Article: PubMed Central - PubMed

Affiliation: Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008, Kazan, Russia.

ABSTRACT

Background: Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation.

Results: In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated.

Conclusions: The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion.

No MeSH data available.


Related in: MedlinePlus