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Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by TRAIL.

Szegezdi E, van der Sloot AM, Mahalingam D, O'Leary L, Cool RH, Muñoz IG, Montoya G, Quax WJ, de Jong S, Samali A, Serrano L - Mol. Cell Proteomics (2012)

Bottom Line: Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling.By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited.It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity.

View Article: PubMed Central - PubMed

Affiliation: School of Natural Sciences, National University of Ireland, Galway, Ireland.

ABSTRACT
Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity.

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Mathematical modeling of TRAIL receptor complex formation triggered by WT TRAIL and D269H/E195R over time.A and B, formation of ligand-bound, homotrimeric DR4, DR5, DcR1, and DcR2 complexes after exposure to WT TRAIL (WT) (A) or D269H/E195R (DE) (B). C and D, homotrimeric DR4 (C) and DR5 (D) formation by theoretical TRAIL variants 1, 2, and 3 (Control-1, Control-2, and Control-3). Control-1 variant binds to DR5 with the affinity of D269H/E195R and with the affinity of WT TRAIL to the other three TRAIL receptors. Control-2 binds to DR5 with the same affinity as WT TRAIL but has the same affinity as D269H/E195R toward DR4, DcR1 and DcR2. Control-3 variant binds to DR5 with 5-fold higher affinity (similar to D269H/E195R) and shows a concurrent equivalent change in affinity toward DR4, DcR1, and DcR2.
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Figure 2: Mathematical modeling of TRAIL receptor complex formation triggered by WT TRAIL and D269H/E195R over time.A and B, formation of ligand-bound, homotrimeric DR4, DR5, DcR1, and DcR2 complexes after exposure to WT TRAIL (WT) (A) or D269H/E195R (DE) (B). C and D, homotrimeric DR4 (C) and DR5 (D) formation by theoretical TRAIL variants 1, 2, and 3 (Control-1, Control-2, and Control-3). Control-1 variant binds to DR5 with the affinity of D269H/E195R and with the affinity of WT TRAIL to the other three TRAIL receptors. Control-2 binds to DR5 with the same affinity as WT TRAIL but has the same affinity as D269H/E195R toward DR4, DcR1 and DcR2. Control-3 variant binds to DR5 with 5-fold higher affinity (similar to D269H/E195R) and shows a concurrent equivalent change in affinity toward DR4, DcR1, and DcR2.

Mentions: When the binding of WT TRAIL to the four TRAIL receptors was simulated, the ½Tmax (i.e. time when 50% of the final response was reached) of the WT TRAIL-3DR5 complex was reached within ∼1100 s, whereas the ½Tmax for DR4 was reached after ∼2300 s (Fig. 2A). The number of WT TRAIL-3DR5 complexes formed after 1 h was the highest, whereas the numbers of TRAIL-3DR4, TRAIL-3DcR1, and TRAIL-3DcR2 were 90, 35, and 1% of the number of TRAIL-3DR5 complexes, respectively. In contrast, the ½Tmax for D269H/E195R-3DR5 complex formation was reached after 130 s, and the amounts of D269H/E195R-3DR4, -3DcR1, or -3DcR2 complexes were much lower even after more than 1 h of simulation (45, 1, and 5%, respectively) (Fig. 2B). The total number of D269H/E195R-3DR5 complexes was ∼15% higher than of WT TRAIL-3DR5 by the end of the simulation.


Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by TRAIL.

Szegezdi E, van der Sloot AM, Mahalingam D, O'Leary L, Cool RH, Muñoz IG, Montoya G, Quax WJ, de Jong S, Samali A, Serrano L - Mol. Cell Proteomics (2012)

Mathematical modeling of TRAIL receptor complex formation triggered by WT TRAIL and D269H/E195R over time.A and B, formation of ligand-bound, homotrimeric DR4, DR5, DcR1, and DcR2 complexes after exposure to WT TRAIL (WT) (A) or D269H/E195R (DE) (B). C and D, homotrimeric DR4 (C) and DR5 (D) formation by theoretical TRAIL variants 1, 2, and 3 (Control-1, Control-2, and Control-3). Control-1 variant binds to DR5 with the affinity of D269H/E195R and with the affinity of WT TRAIL to the other three TRAIL receptors. Control-2 binds to DR5 with the same affinity as WT TRAIL but has the same affinity as D269H/E195R toward DR4, DcR1 and DcR2. Control-3 variant binds to DR5 with 5-fold higher affinity (similar to D269H/E195R) and shows a concurrent equivalent change in affinity toward DR4, DcR1, and DcR2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3316727&req=5

Figure 2: Mathematical modeling of TRAIL receptor complex formation triggered by WT TRAIL and D269H/E195R over time.A and B, formation of ligand-bound, homotrimeric DR4, DR5, DcR1, and DcR2 complexes after exposure to WT TRAIL (WT) (A) or D269H/E195R (DE) (B). C and D, homotrimeric DR4 (C) and DR5 (D) formation by theoretical TRAIL variants 1, 2, and 3 (Control-1, Control-2, and Control-3). Control-1 variant binds to DR5 with the affinity of D269H/E195R and with the affinity of WT TRAIL to the other three TRAIL receptors. Control-2 binds to DR5 with the same affinity as WT TRAIL but has the same affinity as D269H/E195R toward DR4, DcR1 and DcR2. Control-3 variant binds to DR5 with 5-fold higher affinity (similar to D269H/E195R) and shows a concurrent equivalent change in affinity toward DR4, DcR1, and DcR2.
Mentions: When the binding of WT TRAIL to the four TRAIL receptors was simulated, the ½Tmax (i.e. time when 50% of the final response was reached) of the WT TRAIL-3DR5 complex was reached within ∼1100 s, whereas the ½Tmax for DR4 was reached after ∼2300 s (Fig. 2A). The number of WT TRAIL-3DR5 complexes formed after 1 h was the highest, whereas the numbers of TRAIL-3DR4, TRAIL-3DcR1, and TRAIL-3DcR2 were 90, 35, and 1% of the number of TRAIL-3DR5 complexes, respectively. In contrast, the ½Tmax for D269H/E195R-3DR5 complex formation was reached after 130 s, and the amounts of D269H/E195R-3DR4, -3DcR1, or -3DcR2 complexes were much lower even after more than 1 h of simulation (45, 1, and 5%, respectively) (Fig. 2B). The total number of D269H/E195R-3DR5 complexes was ∼15% higher than of WT TRAIL-3DR5 by the end of the simulation.

Bottom Line: Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling.By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited.It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity.

View Article: PubMed Central - PubMed

Affiliation: School of Natural Sciences, National University of Ireland, Galway, Ireland.

ABSTRACT
Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity.

Show MeSH
Related in: MedlinePlus