RESUMEN
The proper orchestration of transforming growth factor beta (TGFß) mediated signal transduction depends upon a delicate set of interactions between specific ligands and their receptors. Here we present an in-depth profiling of the binding mechanism of TGFß3 ligand with its type II and type I receptors (TßRII and TßRI) using isothermal titration calorimetry (ITC). Studies were carried out in acidic pH as it has great physiological relevance for TGFß3 activity. Our findings reveal an unusual positive enthalpy (∆H) compensated by a large favourable entropy (∆S) during TGFß3-TßRII interaction. In addition to the hydrophobic effect, we propose that a distinct conformational switch from "closed" to "open" form as experienced by TGFß3 on binding to TßRII is contributing significantly to the increase in overall entropy of the system. Binding studies of TGFß3 and TßRII were carried out at different pH values and salt concentrations to gain further insight into the thermodynamics of the interaction. Furthermore, the importance of hydrophobic interactions on the binding affinity of TßRII with TGFß3 was confirmed by two TßRII variants (interfacial). Finally, a distinct shift from entropy to enthalpy dominated interaction was observed upon recruitment of TßRI to the binary complex forming the ternary complex.