Interleukin-6 (IL-6) triggers the formation of a high affinity receptor complex constituted by the ligand-binding subunit IL-6 receptor α (IL-6Rα) and the signal-transducing β chain gp130. Since the cytoplasmic region of IL-6Rα is not required for signal transduction, soluble forms of IL-6Rα (sIl-6Rα) show agonistic properties because they are still able to originate IL-6·sIL-6Rα complexes, which in turn associate with gp130. A three- dimensional model of the human IL-6·IL-6Rα·gp130 complex has been constructed and verified by site-directed mutagenesis of regions in shIL- 6Rα (where 'h' is human) anticipated to contact hgp130, with the final goal of generating receptor variants with antagonistic properties. In good agreement with our structural model, substitutions at Asn-230, His-280, and Asp-281 selectively impaired the capability of shIL-6Rα to associate with hgp130 both in vitro and on the cell surface, without affecting its affinity for hIL-6. Moreover, the multiple substitution mutant A228D/N230D/H280S/D281V expressed as a soluble protein partially antagonized hIL-6 bioactivity on hepatoma cells.
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