The role of asymmetric binding in ligand-receptor systems with 1:2 interaction ratio

Dynamical models for cellular ligand-receptor systems are among the most successful examples of mathematical approaches in systems biology. Here we present a general kinetic and mechanistic model for systems with asymmetric 1:2 ligand-receptor interaction ratio, such as erythropoietin and growth hormone systems. In these systems, the ligand presents two very different binding affinities to its receptor, and the weak interaction being often neglected for modeling purposes. Here, we demonstrate that the weak binding is the one tightly regulating the signaling, while the strong binding sets the threshold for the auto-inhibition effect characteristic of 1:2 asymmetric ligand-receptor systems. The model constitutes an improved mathematical framework for erythropoietin activation and equivalent biological processes, which are, due to their widespread use and relevance, on the forefront of pharmacological systems biology.