(1) Molecular modelling group, Ludwig Institute for Cancer Research and The
Cooperative Research Centre for Cellular Growth Factors, PO Royal Melbourne
Hospital, Parkville, Victoria, 3050, Australia
(2) Department of Biochemistry,
Hong kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong
The helical cytokines are a group of proteins involved in the neuropoietic, haemopietic and immune systems. They exert a wide range of effects on many cell types and have several current and potential therapeutic uses. While the three dimensional structures of thirteen helical cytokines are known at present, much less is known about the structures of their receptor complexes. To date, the only complete cytokine /extracellular receptor complex known is that of growth hormone (de Vos et al., 1992). Recently, though, it has been shown that the receptor complexes of Interleukin-6 (IL-6) and Ciliary Neurotrophic Factor (CNTF) are hexameric (Ward etal., 1994; Paonessa et al., 1995, de Serio et al., 1995). As the amount of mutagenesis data on the helical cytokines and their receptors is steadily increasing it is now possible to provide explanations for much of the biological data in terms of structural models of cytokine/ receptor complexes.
This work uses structural insights gained from homology modelling studies of the Leukaemia Inhibitory Factor (LIF) receptor, gp130 and the Granulocyte Colony-Stimulating Factor (G-CSF) receptor and the available biochemical data to construct models of the receptor complexes of IL-6, CNTF and G-CSF. These models are consistent with the available mutagenesis and receptor domain deletion mutant data. They provide a coherent explanation for the range of experimental data currently available and suggest further experimentation which could verify the proposals of the models. A feature of these models is that they suggest that IL-6, CNTF and G-CSF have receptor complexes that are related structurally. This could represent an evolutionary relationship amongst the helical cytokines which would help to explain their overlaping functions.
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Ward et al., (1994) J. Biol. Chem, 269: 23286-23289