Identification of Single Amino Acid Residues of Human IL-6 Involved in Receptor Binding and Signal Initiation

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Abstract
The pleiotropic cytokine interleukin-6 (IL-6) has been predicted to be a protein with four antiparallel α-helices. On target cells, IL-6 interacts with a specific ligand binding receptor subunit (IL-6R), and this complex associates with the signal-transducing subunit gp130. Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction of chimeric human/murine IL-6 proteins has allowed us to define a region (residues 77-95, region 2c) within the human IL-6 protein that is important for IL-6R binding and a region (residues 50-55, region 2a2) that is important for IL-6R-dependent gpl30 interaction. Guided by sequence alignment and molecular modeling, we have constructed several IL-6 variants with point mutations in these regions and have tested them for receptor binding and signal initiation. Within region 2c, phenvlalanine 78 was involved in receptor binding, whereas lysine 54 within region 2a2 participated in gpl30 activation. Furthermore, some IL-6 variants with lysine 54 replacements could be used to construct muteins that retained receptor binding but failed to activate gpl30. Such IL-6 muteins were efficient IL-6 receptor antagonists.