Abstract
Interleukin-6 (IL-6) drives the sequential assembly of a receptor complex formed by the IL-6 receptor (IL-6Rα) and the signal transducing subunit, gp130. A model of human IL-6 (hIL-6), was constructed by homology using the structure of bovine granulocyte colony stimulating factor. The modeled cytokine was predicted to interact sequentially with the cytokine binding domains of IL-6Rα and gp130 bridging them in a way similar to that of the interaction between growth hormone and its homodimeric receptor. Several residues on helices A and C which were predicted as contact points between IL-6 and gp130 and therefore essential for IL-6 signal transduction, were subjected to site-directed mutagenesis individually or in combined form. Interestingly, while single amino acid changes never produced major alterations in IL-6 bioactivity, a subset of double mutants of Y31 and G35 showed a considerable reduction of biological activity and were selectively impaired from associating with gp130 in binding assays in vitro, while they maintained wild-type affinity towards hIL6-Rα. More importantly, we demonstrated the antagonistic effect of mutant Y31D/G35F versus wild-type IL-6.
Original language | English |
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Pages (from-to) | 1357-1367 |
Number of pages | 11 |
Journal | EMBO Journal |
Volume | 13 |
Issue number | 6 |
Publication status | Published - Mar 15 1994 |
Keywords
- Antagonist
- gp130 interaction
- Interleukin-6
- Molecular modeling
- Mutagenesis
ASJC Scopus subject areas
- Cell Biology
- Genetics