Participation of two Ser-Ser-Phe-Tyr repeats in interleukin-6 (IL-6)-binding sites of the human IL-6 receptor.
The alpha-subunit of interleukin-6 (IL-6) receptor is a member of the hematopoietin receptor family. The alignment of its amino acid sequence with those of other members of this family (human somatotropin receptor/murine IL-3 receptor beta and human IL-2 receptor beta) has suggested that amino acids included in two SSFY repeats found in each of its hematopoietin receptor domains, contribute to the binding of the ligand. The involvement of these amino acids in IL-6 binding and signal transduction was studied by site-directed mutagenesis and molecular modelling. We present a computer-derived three-dimensional model of the IL-6/IL-6 receptor complex based on the structure of the human somatotropin/human somatotropin receptor complex. This model allowed the location of distinct regions important for IL-6 and gp130 binding. We show that some of the residues included in the SSFY repeats located in our IL-6 receptor model in the loops between beta-strands E and F of domain-I and B' and C', of domain-II, participate in the formation of a major IL-6-binding site. These residues are necessary for IL-6 and gp130 binding and for signal transduction. Using our IL-6 receptor mutants we mapped the epitopes of our anti-(IL-6 receptor) neutralising monoclonal antibodies to these residues. Our results demonstrate that a generic hematopoietin receptor family structural module can be used for the study of both alpha and beta receptor subunits belonging to this family.
Kalai
M
M
Institut Pasteur de Bruxelles, Départment de Virologie, Bruxelles, Belgium.
Montero-Julian
F A
FA
Grötzinger
J
J
Wollmer
A
A
Morelle
D
D
Brochier
J
J
Rose-John
S
S
Heinrich
P C
PC
Brailly
H
H
Content
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D018604:Epitope Mapping; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011817:Rabbits; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D019947:Receptors, Interleukin-6; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6