Structural and biophysical studies of the human IL-7/IL-7Ralpha complex.
IL-7 and IL-7Ralpha 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-7Ralpha 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-7Ralpha 300-fold more tightly than unglycosylated IL-7Ralpha, and the enhanced affinity is attributed primarily to an accelerated on rate. Structural comparison of IL-7 in complex to both forms of IL-7Ralpha reveals that glycosylation does not participate directly in the binding interface. The SCID mutations of IL-7Ralpha locate outside the binding interface with IL-7, suggesting that the expressed mutations cause protein folding defects in IL-7Ralpha. The IL-7/IL-7Ralpha 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.
McElroy
Craig A
CA
Department of Molecular and Cellular Biochemistry, College of Medicine, Comprehensive Cancer Center, Ohio State University, 467 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.
Dohm
Julie A
JA
Walsh
Scott T R
ST
D001703:Biophysics; D015374:Biosensing Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D006031:Glycosylation; D006801:Humans; D015851:Interleukin-7 / Q000737:chemistry*; D053699:Interleukin-7 Receptor alpha Subunit / Q000737:chemistry*; D011487:Protein Conformation
D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit