Identification of two novel regions of human IL-6 responsible for receptor binding and signal transduction.
The pleiotropic cytokine IL-6 has been predicted to be a protein with four antiparallel alpha-helices. Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction of a set of chimeric human/murine IL-6 proteins has recently allowed us to define a new region (residues Lys41-Glu95) within the IL-6 molecule as being important for receptor binding and biologic activity. We subdivided and analyzed this region, which primarily corresponds to the loop between the first and second alpha-helix of IL-6 with respect to its role in the interaction with the ligand binding subunit of the IL-6 receptor complex and with the IL-6 signal-transducing protein gp130. By construction and analysis of human/murine chimeric IL-6 molecules with only 7 to 10 amino acid residues different from human IL-6 we show that two distinct parts of this region are responsible for receptor binding and signal transduction. On the basis of the recently published structure of granulocyte-CSF, we present a three-dimensional model for the tertiary structure of IL-6, which, together with the IL-6 receptor interaction data, allows for the rational design of human IL-6 receptor antagonists.
Ehlers
M
M
Department of Biochemistry, Rhein-Westphalian Technical College Aachen, Germany.
Grötzinger
J
J
deHon
F D
FD
Müllberg
J
J
Brakenhoff
J P
JP
Liu
J
J
Wollmer
A
A
Rose-John
S
S
D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000378:metabolism; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D000093242:Interleukin-6 Inhibitors
D017931:DNA Primers; D016179:Granulocyte Colony-Stimulating Factor; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D000093242:Interleukin-6 Inhibitors