Structural reorganization of the interleukin-7 signaling complex

We report here an unliganded receptor structure in the common gamma-chain (gamma(c)) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7R alpha) extracellular domain (ECD) at 2.15 angstrom resolution reveals a homodimer forming an X geometry looking down onto the cell surface with the C termini of the two chains separated by 110 angstrom and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Ra ECDs but a stronger association between the gamma(c)/IL-7R alpha ECDs, similar to previous studies of the full-length receptors on CD4(+) T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7R alpha homodimer and IL-7R alpha-gamma(c) heterodimer to the active IL-7-IL-7R alpha-gamma(c) ternary complex whereby the two receptors undergo at least a 90 degrees rotation away from the cell surface, moving the C termini of IL-7R alpha and gamma(c) from a distance of 110 angstrom to less than 30 angstrom at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7- and gamma(c)-independent gain-of-function mutations in IL-7Ra from B-and T-cell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other gamma(c) receptors that form inactive homodimers and heterodimers independent of their cytokines.