Cutting edge: Identification of a pre-ligand assembly domain (PLAD) and ligand binding site in the IL-17 receptor

IL-17 is the hallmark cytokine of the newly described Th17 lymphocyte population. The composition, subunit dynamics, and ligand contacts of the IL-17 receptor are poorly defined. We previously demonstrated that the IL-17RA subunit oligomerizes in the membrane without a ligand, In this study, computational modeling identified two fibronectin-III-like (FN) domains in IL-17RA connected by a nonstructured linker, which we predicted to mediate homotypic interactions. In yeast two-hybrid, 'proximal FN domain (FN2), but not the membrane the membrane-distal domain (FNI), formed homomeri. c interactions. The ability of FN2 to drive ligand-independent multimerization was verified by coimmunoprecipitation and fluorescence resonance energy no transfer microscopy. Thus, FN2 constitutes a pre-ligand assembly domain (PLAD). Further studies indicated that the FN2 linker domain contains the IL-17 binding site, which was never mapped. However, the FNI domain is also required for high affinity interactions with IL-17. Therefore, although the PLAD is located entirely within FN2, effective ligand binding also involves contributions from the linker and FN1.