Probing the Relationship between Extracellular Ligand Recognition and Cytokine Receptor Activation with Structural Biology and Protein Engineering

The question of whether cytokines can deliver ‘instructive’ signals through their interactions with the cytokine receptor extracellular domains remains an unsolved, but important question. While every cytokine receptor system to date exhibits some form of ligand-dependent oligomerization as a prerequisite for activation, it is unclear if the specific nuances of the recognition chemistry and extracellular domain-cytokine complex architecture play a role in modulating the specificity of signaling. Our group is exploring this questions in shared cytokine receptor systems such as Interferon, gp130/IL-12, and common gamma chain through an integration of structural studies to directly image the cytokine-receptor complexes, and engineering studies aimed at influencing signaling through introducing chemical and structural perturbations. In my talk I will present recent results from these studies bearing on the issue of ligand-based tuning of cytokine receptor signaling.