Saturation mutagenesis of the human interleukin 6 receptor-binding site: Implications for its three-dimensional structure

R. Savino, A. Lahm, M. Giorgio, A. Cabibbo, A. Tramontano, G. Ciliberto

Research output: Contribution to journalArticle

Abstract

Interleukin 6 is a 184-aa polypeptide postulated to belong to the class of helical cytokines. We built a three-dimensional model of human interleukin 6 based on the similarity of its hydrophobicity pattern with that of other cytokines and on the x-ray structure of growth hormone, interleukin 2, interleukin 4, interferon β, and granulocyte-macrophage colony-stimulating factor. The resulting model is a bundle of four α-helices and suggests possible alternative conformations for the 9 C-terminal amino acids; in this region, the importance of Arg-182 and Met-184 for biological activity has been demonstrated [Lutticken, C., Kruttgen, A., Moller, C., Heinrich, P. C. & Rose-John, S. (1991) FEBS Lett. 282, 265-267]. Therefore, we generated a large collection of single-amino acid variants in residues 175-181. Analysis of their biological activity in two systems and the receptor binding properties of a subset of the mutants indicates that the entire region is involved in forming the receptor binding surface and supports the hypothesis that this region does not assume an α-helical conformation. Remarkably, we also found a mutant with receptor affinity and biological activity much higher than wild type; the potential therapeutical value of this finding is discussed.

Original languageEnglish
Pages (from-to)4067-4071
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number9
Publication statusPublished - May 1 1993

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ASJC Scopus subject areas

  • General
  • Genetics

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