Structural and Biophysical Studies of the Human IL-7/IL-7Rα Complex

IL-7 and IL-7R alpha bind the gamma(c) receptor, forming a complex crucial to several signaling cascades leading to the development and homeostasis of T and B cells. We report that the IL-7R alpha ectodomain uses glycosylation to modulate its binding constants to IL-7, unlike the other receptors in the gamma(c) family. IL-7 binds glycosylated IL-7R alpha 300-fold more tightly than unglycosylated IL-7R alpha, and the enhanced affinity is attributed primarily to an accelerated on rate. Structural comparison of IL-7 in complex to both forms of IL-7R alpha reveals that glycosylation does not participate directly in the binding interface. The SCID mutations of IL-7R alpha locate outside the binding interface with IL-7, suggesting that the expressed mutations cause protein folding defects in IL-7R alpha. The IL-7/IL-7R alpha structures provide a window into the molecular recognition events of the IL-7 signaling cascade and provide sites to target for designing new therapeutics to treat IL-7-related diseases.