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
Highlights
To enable diverse biological responses, many ligand-receptor systems consist of multiple receptors and/or ligands [1,2,3,4]
The response can be dictated by the final equilibrium distribution of the ligand with the different receptors, but it is possible that the biological effect is more dynamically driven by temporal kinetic effects of the ligand interacting with its receptors [5]
Mathematical Modeling of Ligand Receptor Interaction—To investigate the hypothesis that the kinetics of receptor activation of promiscuous ligand receptor systems is governed by nonproductive heteromeric interactions and that the kinetics of such systems could be modified by changing specificity, we simulated the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) ligand receptor interaction occurring on the cell surface using a mathematical model
Summary
To enable diverse biological responses, many ligand-receptor systems consist of multiple receptors and/or ligands [1,2,3,4]. In principle, excluding well known effects like macromolecular crowding or protein immobilization, one could assume that it should be possible to extrapolate kinetic and equilibrium constants from in vitro to in vivo conditions, provided that the in vitro conditions reflect the in vivo ones This simple assumption could fail if the molecule that triggers a signal can be trapped in nonproductive interactions that equilibrate slowly with the productive complex. This can significantly slow down or even block the progression of a signal In such cases, one could imagine that increasing the specificity of the ligand toward the productive complex could result in faster kinetics of receptor activation [7]. With the ligand-dependent or ligandindependent DcR2/DR4/5 hetero-oligomerization, the equilibrium distribution between the receptors will not be changed much because of these affinity differences and cannot be responsible for observed antagonistic effects either
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