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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

Temporal characteristics of the apo- and fully bound species in response to a ligand jump. The dynamics of the concentration of proteins was investigated for apo- (a) and fully bound (b) forms in response to the non-dimensional ligand concentration change from U0/K = 0.1 to U1/K = 10 as a function of non-dimensional time η = t ⋅ k−. The dotted lines indicate the time, τ00.5, required for the non-dimensional concentration of apo- conformation, N0/LT, to reach half of the fall in concentration and the period of time, τ40.5, that takes for the fully saturated protein species, N4/LT, to gain half of the growth in concentration. These kinetic parameters then were subject to the investigation as a function of the initial (c) and final (d) ligand concentrations. The presented analysis clearly demonstrates the bell shaped dependence of τ40.5 on the final ligand concentration
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Fig3: Temporal characteristics of the apo- and fully bound species in response to a ligand jump. The dynamics of the concentration of proteins was investigated for apo- (a) and fully bound (b) forms in response to the non-dimensional ligand concentration change from U0/K = 0.1 to U1/K = 10 as a function of non-dimensional time η = t ⋅ k−. The dotted lines indicate the time, τ00.5, required for the non-dimensional concentration of apo- conformation, N0/LT, to reach half of the fall in concentration and the period of time, τ40.5, that takes for the fully saturated protein species, N4/LT, to gain half of the growth in concentration. These kinetic parameters then were subject to the investigation as a function of the initial (c) and final (d) ligand concentrations. The presented analysis clearly demonstrates the bell shaped dependence of τ40.5 on the final ligand concentration

Mentions: Figure 3 shows the calculations for the temporal characteristics of the apo- and fully bound species. Figure 3a and b show that the temporal shapes of the apo- and fully bound conformations (Eqs. (19) in Methods) in response to a ligand change are similar to the steady-state dependence of the same conformations on ligand concentration [24]. The kinetic parameters, τ00.5 and τ40.5 can be estimated as the time required to reach 50 % of the total concentration (Fig. 3a and b). The described kinetic parameters have been investigated as a function of the initial and final ligand concentrations (Fig. 3c, d and Eqs. (24) in Methods). Our analysis reveals a reduction of the time constant, τ00.5, of the apo- conformation with the reduction of the initial ligand concentration and an increase of the final ligand concentration. However, the dependence of the characteristic time τ40.5 (Fig. 3d) showed an unexpected bell shaped dependence on the final ligand concentration compared to the simpler monotonic dependence for τ00.5 (Fig. 3c). The model predicts that there is an “optimal” ligand concentration for the saturation effect to take the longest time (Fig. 3d).Fig. 3


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)

Temporal characteristics of the apo- and fully bound species in response to a ligand jump. The dynamics of the concentration of proteins was investigated for apo- (a) and fully bound (b) forms in response to the non-dimensional ligand concentration change from U0/K = 0.1 to U1/K = 10 as a function of non-dimensional time η = t ⋅ k−. The dotted lines indicate the time, τ00.5, required for the non-dimensional concentration of apo- conformation, N0/LT, to reach half of the fall in concentration and the period of time, τ40.5, that takes for the fully saturated protein species, N4/LT, to gain half of the growth in concentration. These kinetic parameters then were subject to the investigation as a function of the initial (c) and final (d) ligand concentrations. The presented analysis clearly demonstrates the bell shaped dependence of τ40.5 on the final ligand concentration
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Temporal characteristics of the apo- and fully bound species in response to a ligand jump. The dynamics of the concentration of proteins was investigated for apo- (a) and fully bound (b) forms in response to the non-dimensional ligand concentration change from U0/K = 0.1 to U1/K = 10 as a function of non-dimensional time η = t ⋅ k−. The dotted lines indicate the time, τ00.5, required for the non-dimensional concentration of apo- conformation, N0/LT, to reach half of the fall in concentration and the period of time, τ40.5, that takes for the fully saturated protein species, N4/LT, to gain half of the growth in concentration. These kinetic parameters then were subject to the investigation as a function of the initial (c) and final (d) ligand concentrations. The presented analysis clearly demonstrates the bell shaped dependence of τ40.5 on the final ligand concentration
Mentions: Figure 3 shows the calculations for the temporal characteristics of the apo- and fully bound species. Figure 3a and b show that the temporal shapes of the apo- and fully bound conformations (Eqs. (19) in Methods) in response to a ligand change are similar to the steady-state dependence of the same conformations on ligand concentration [24]. The kinetic parameters, τ00.5 and τ40.5 can be estimated as the time required to reach 50 % of the total concentration (Fig. 3a and b). The described kinetic parameters have been investigated as a function of the initial and final ligand concentrations (Fig. 3c, d and Eqs. (24) in Methods). Our analysis reveals a reduction of the time constant, τ00.5, of the apo- conformation with the reduction of the initial ligand concentration and an increase of the final ligand concentration. However, the dependence of the characteristic time τ40.5 (Fig. 3d) showed an unexpected bell shaped dependence on the final ligand concentration compared to the simpler monotonic dependence for τ00.5 (Fig. 3c). The model predicts that there is an “optimal” ligand concentration for the saturation effect to take the longest time (Fig. 3d).Fig. 3

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