Structure-activity Relationships of The IL-2/IL-2R Interaction
Detailed experiments over a decade (1990s) using a rigorous reductionist approach with isolated purified receptor chains and Surface plasmon resonance revealed that the alpha chain of the IL-2R can bind to the beta chain before receptor interaction with IL-2, and that the IL-2Rα/β heterodimer formed has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone. The gamma chain alone has a very weak affinity for IL-2 (Kd > 700 uM), but after IL-2 is bound to the α/β heterodimer, the gamma chain becomes recruited to the IL2/IL2R complex to form a very stable macromolecular quaternary ligand/receptor complex. These data were recently confirmed and extended by energetics experiments using Isothermal Titration Calorimetry and Multi-Angle Light Scattering.
The 3-dimensional structure of the three IL-2R chains binding IL-2 was determined by X-ray crystallography.
The sites on the IL-2 molecule that interact with the three receptor chains do not overlap, except for a small but significant region. The IL-2 molecule is composed of four antiparallel alpha helices and it is held between the beta and gamma chains, which converge to form a Y shape; IL-2 is held in the fork of the Y. The other side of the IL-2 molecule binds to the IL-2R alpha chain. The alpha chain itself does not contact either beta or gamma chain of the IL-2R. Following the binding of IL-2, the beta chain undergoes a conformational change that evidently increases its affinity for the gamma chain, thereby attracting it to form a stable quaternary molecular complex.
Read more about this topic: IL-2 Receptor
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