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Analysis of the human interleukin-6/human interleukin-6 receptor binding
interface at the amino acid level: proposed mechanism of interaction
M Kalai, FA Montero-Julian, J Grotzinger, V Fontaine, P Vandenbussche, R Deschuyteneer, A Wollmer, H Brailly and J Content
Institut Pasteur de Bruxelles, Departement de Virologie, Belgium.
The interaction between interleukin-6 (IL-6) and IL-6 receptor (IL-6R) is
the initial and most specific step in the IL-6 signaling pathway.
Understanding its mechanism at the amino acid level is the basis for
developing small IL-6-inhibiting molecules. We studied the human IL-6
(hIL-6)/hIL-6R binding interface by a combination of molecular modelling
and site-directed mutagenesis. Our model suggests that the center of the
interface between the two molecules consists of hydrophobic contacts
predicted to account for most of the binding-free energy. These contacts
can be regarded as a hydrophobic core shielded by hydrophilic residues that
are also needed for recognition. Following this hypothesis, we altered in
hIL-6 and hIL-6R residues predicted to reside in the contact region and to
interact with each other. We studied the capacity of these mutants to form
an IL-6/IL-6R complex and their ability to transduce the signal. This
combined approach has led to the identification of certain residue-clusters
in the binding interface and to a rational explanation of their specific
interactions, suggesting therein a likely mechanism of complex formation.
The results confirm the predictive model and strongly support our
hypothesis. Comparison with other cytokines and their alpha-subunit
receptors suggests that the structural location of certain binding sites
are conserved.
Volume 89,
Issue 4,
pp. 1319-1333,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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