Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6
| Autor: | K J, Kallen, J, Grötzinger, E, Lelièvre, P, Vollmer, D, Aasland, C, Renné, J, Müllberg, K H, Myer zum Büschenfelde, H, Gascan, S, Rose-John |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Lymphokines Binding Sites Leukemia Inhibitory Factor Receptor alpha Subunit Receptors OSM-LIF Interleukin-6 Protein Conformation Recombinant Fusion Proteins Nerve Tissue Proteins Leukemia Inhibitory Factor Growth Inhibitors Epitopes COS Cells Tumor Cells Cultured Animals Humans Ciliary Neurotrophic Factor Phosphorylation Receptors Cytokine |
| Zdroj: | The Journal of biological chemistry. 274(17) |
| ISSN: | 0021-9258 |
| Popis: | Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) are "4-helical bundle" cytokines of the IL-6 type family of neuropoietic and hematopoietic cytokines. IL-6 signals by induction of a gp130 homodimer (e.g. IL-6), whereas CNTF and leukemia inhibitory factor (LIF) signal via a heterodimer of gp130 and LIF receptor (LIFR). Despite binding to the same receptor component (gp130) and a similar protein structure, IL-6 and CNTF share only 6% sequence identity. Using molecular modeling we defined a putative LIFR binding epitope on CNTF that consists of three distinct regions (C-terminal A-helix/N-terminal AB loop, BC loop, C-terminal CD-loop/N-terminal D-helix). A corresponding gp130-binding site on IL-6 was exchanged with this epitope. The resulting IL-6/CNTF chimera lost the capacity to signal via gp130 on cells without LIFR, but acquired the ability to signal via the gp130/LIFR heterodimer and STAT3 on responsive cells. Besides identifying a specific LIFR binding epitope on CNTF, our results suggest that receptor recognition sites of cytokines are organized as modules that are exchangeable even between cytokines with limited sequence homology. |
| Databáze: | OpenAIRE |
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