Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 12242-12249 |
| Number of pages | 8 |
| Journal | Journal of Biological Chemistry |
| Volume | 270 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - 1995 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Interleukin-6 (IL-6) antagonism by soluble IL-6 receptor α mutated in the predicted gp130-binding interface. / Salvati, A. L.; Lahm, A.; Paonessa, G.; Ciliberto, G.; Toniatti, C.
In: Journal of Biological Chemistry, Vol. 270, No. 20, 1995, p. 12242-12249.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Interleukin-6 (IL-6) antagonism by soluble IL-6 receptor α mutated in the predicted gp130-binding interface
AU - Salvati, A. L.
AU - Lahm, A.
AU - Paonessa, G.
AU - Ciliberto, G.
AU - Toniatti, C.
PY - 1995
Y1 - 1995
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=0029019013&partnerID=8YFLogxK
U2 - 10.1074/jbc.270.20.12242
DO - 10.1074/jbc.270.20.12242
M3 - Article
C2 - 7744875
AN - SCOPUS:0029019013
VL - 270
SP - 12242
EP - 12249
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 20
ER -