Definition of a composite binding site for gp130 in human interleukin-6

Laura Ciapponi, Rita Graziani, Giacomo Paonessa, Armin Lahm, Gennaro Ciliberto, Rocco Savino

Research output: Contribution to journalArticle

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Abstract

The helical cytokine interleukin-6 (IL-6) assembles a multiprotein receptor complex. The starting event in the activation of intracellular signaling is the binding of the IL-6/IL-6Rα subcomplex to two gp130 chains. The homodimerization of gp130 is triggered by two distinct and independent regions of IL-6 called sites 2 and 3. Several IL-6 antagonists have been obtained that affect signaling, but not IL-6·IL-6Rα subcomplex formation. In this paper, we analyze in detail the impact of these antagonists on gp130 binding and dimerization and show that each signaling variant affects gp130 dimerization in vitro and that biological activity on cells decreases in precise parallel to the decrease in gp130 dimerization in vitro. All IL-6 antagonists can be classified into two groups, mapping at either site 2 or 3 in correspondence to their mode of interaction with gp130. We found that site 3 is a large region, which includes residues at the beginning of helix D spatially flanked by residues in the putative AB loop and located at one extremity of the cytokine 4-helix bundle. Interestingly, in leukemia inhibitory factor, another cytokine that signals through gp130, site 3, is topologically conserved but has evolved to bind leukemia inhibitory factor receptor.

Original languageEnglish
Pages (from-to)31249-31254
Number of pages6
JournalJournal of Biological Chemistry
Volume270
Issue number52
DOIs
Publication statusPublished - Dec 29 1995

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Interleukin-6
Binding Sites
Dimerization
Composite materials
Cytokines
OSM-LIF Receptors
Leukemia Inhibitory Factor
Multiprotein Complexes
Bioactivity
Extremities
Chemical activation
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry

Cite this

Definition of a composite binding site for gp130 in human interleukin-6. / Ciapponi, Laura; Graziani, Rita; Paonessa, Giacomo; Lahm, Armin; Ciliberto, Gennaro; Savino, Rocco.

In: Journal of Biological Chemistry, Vol. 270, No. 52, 29.12.1995, p. 31249-31254.

Research output: Contribution to journalArticle

Ciapponi, L, Graziani, R, Paonessa, G, Lahm, A, Ciliberto, G & Savino, R 1995, 'Definition of a composite binding site for gp130 in human interleukin-6', Journal of Biological Chemistry, vol. 270, no. 52, pp. 31249-31254. https://doi.org/10.1074/jbc.270.52.31249
Ciapponi, Laura ; Graziani, Rita ; Paonessa, Giacomo ; Lahm, Armin ; Ciliberto, Gennaro ; Savino, Rocco. / Definition of a composite binding site for gp130 in human interleukin-6. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 52. pp. 31249-31254.
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