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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

Characteristic time required for intermediate conformations to reach their maximum levels as a function of the step change magnitude. The analysis shows that the non-dimensional time (ηmmax = τmmaxk−, where m = 1, 2 and 3) required for reaching the maximum level of the intermediate species, is inversely proportional to the concentration of the applied ligand U1/K. This effect is due to the growing abundance of the free ligand concentration available for faster interaction with the multisite protein
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Fig4: Characteristic time required for intermediate conformations to reach their maximum levels as a function of the step change magnitude. The analysis shows that the non-dimensional time (ηmmax = τmmaxk−, where m = 1, 2 and 3) required for reaching the maximum level of the intermediate species, is inversely proportional to the concentration of the applied ligand U1/K. This effect is due to the growing abundance of the free ligand concentration available for faster interaction with the multisite protein

Mentions: Figure 4 shows the dependence of the time point τmmaxk− when the intermediate protein conformations reach the maximum as a function of magnitude of ligand jump (Eqs. (26) in Methods). It can be seen from Eqs. (26) that τ1maxk−, τ2maxk− and τ3maxk− do not exist for , U1/K < 1 and U1/K < 3, respectively. Under these special cases, where the ligand concentration U1/K is not sufficient for the concentrations of the intermediate conformations to reach their maximal values, these concentrations monotonously grow to their respective steady-state levels. According to Eq. (26), the values U1/K < 1 and U1/K < 3 correspond to the three individual intermediate conformations with one, two and three bound sites respectively.Fig. 4


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)

Characteristic time required for intermediate conformations to reach their maximum levels as a function of the step change magnitude. The analysis shows that the non-dimensional time (ηmmax = τmmaxk−, where m = 1, 2 and 3) required for reaching the maximum level of the intermediate species, is inversely proportional to the concentration of the applied ligand U1/K. This effect is due to the growing abundance of the free ligand concentration available for faster interaction with the multisite protein
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Characteristic time required for intermediate conformations to reach their maximum levels as a function of the step change magnitude. The analysis shows that the non-dimensional time (ηmmax = τmmaxk−, where m = 1, 2 and 3) required for reaching the maximum level of the intermediate species, is inversely proportional to the concentration of the applied ligand U1/K. This effect is due to the growing abundance of the free ligand concentration available for faster interaction with the multisite protein
Mentions: Figure 4 shows the dependence of the time point τmmaxk− when the intermediate protein conformations reach the maximum as a function of magnitude of ligand jump (Eqs. (26) in Methods). It can be seen from Eqs. (26) that τ1maxk−, τ2maxk− and τ3maxk− do not exist for , U1/K < 1 and U1/K < 3, respectively. Under these special cases, where the ligand concentration U1/K is not sufficient for the concentrations of the intermediate conformations to reach their maximal values, these concentrations monotonously grow to their respective steady-state levels. According to Eq. (26), the values U1/K < 1 and U1/K < 3 correspond to the three individual intermediate conformations with one, two and three bound sites respectively.Fig. 4

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