Part:BBa_K4040032
IL-6 signal transducer, gp130
Sequence and Features
- 10COMPATIBLE WITH RFC[10]
- 12COMPATIBLE WITH RFC[12]
- 21COMPATIBLE WITH RFC[21]
- 23COMPATIBLE WITH RFC[23]
- 25COMPATIBLE WITH RFC[25]
- 1000COMPATIBLE WITH RFC[1000]
Usage and Biology
Membrane glycoprotein 130 (gp130) is also known as IL-6R-beta, CD130, which is single-pass type I membrane protein. GP130 can be found in tissues such as brain, heart, thymus, spleen, kidney, lung and liver and found in all the cell lines tested except BaF-B03.The expression of gp130 is not restricted to IL6-responsive cells. The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize gp130 for initiating signal transmission. GP130 can bind to IL6 /IL6R (alpha chain) complex, resulting in the formation of high-affinity IL6 binding sites, and transduce the signal. GP130 does not bind IL6 and may have a role in embryonic development. We use this part to build the synthetic IL-6R in order to transduct the signal by forming a hexamer with IL-6 and mIL-6R.
Background and detail description
Signalling pathway of gp130
mgp130 (membrane-bound gp130) is expressed ubiquitously in the body. Therefore the IL-6-sIL-6R complex could, theoretically, stimulate most cells in the body. However, this trans-signalling is thought to be highly regulated by sgp130 (soluble gp130), which exists in higher concentrations in circulating blood. IL-6 binds to IL-6R with an affinity of 10−9 to 10−10mol/l and gp130 binds to IL-6–sIL-6R complex with an affinity of 10−11mol/l [1,2–4]. In fact, TCZ can dissociate the IL-6–sIL-6R complex, but not the IL-6–sIL-6R–sgp130 complex, suggesting that the IL-6–sIL-6R complex is more rigid than the IL-6–sIL-6R–sgp130 complex [5]. gp130 is used in the signalling of many other members of the IL-6 family of cytokines, including LIF (leukaemia inhibitory factor), CNTF (ciliary neurotrophic factor), OSM (oncostatin M), CT-1 (cardiotrophin-1), CLC(cardiotrophin-like related cytokine), also known as NNT-1 (novel neurotrophin-1) or BSF-3, NPN(neuropoietin), IL-11 and IL-27 [6–8]. The sharing of the gp130 molecule by other IL-6 superfamily cytokines may explain their functional redundancy. A similar system can also be seen within the other cytokine families; for example, the group of cytokines comprising IL-3, IL-5 and GM-CSF (granulocyte/macrophage colony-stimulating factor) uses a common β receptor, and the group of ILs including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 uses a common γ receptor component[9]. The structure of the gp130–IL-6R–IL-6 complex has been solved by X-ray crystallography: it is a hexamer comprising two IL-6, two IL-6R and two gp130 proteins[10]. It has been argued, however, that the signalling complex is built of one IL-6–IL-6R complex bound to two gp130 proteins [11].
Used for a synthetic IL-6 receptor
When the concentration of IL-6 in the body increases to a certain level, IL-6 binds to mIL-6R (membrane-bound IL-6R), homodimerization of gp130 is induced, and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed, causing the release of transcription factors, which triggers the subsequent pathway.
References
[1]Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T. and Kishimoto, T. (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149–1157
[2]Taga, T., Kawanishi, Y ., Hardy, R. R., Hirano, T. and Kishimoto, T. (1987) Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression. J. Exp. Med. 166, 967–981
[3]Stoyan, T., Michaelis, U., Schooltink, H., Van Dam, M., Rudolph, R., Heinrich, P . C. and Rose-John, S. (1993) Recombinant soluble human interleukin-6 receptor. Expression in Escherichia coli, renaturation and purification. Eur. J. Biochem. 216, 239–245
[4]Rose-John, S., Hipp, E., Lenz, D., Legres, L. G., Korr, H., Hirano, T., Kishimoto, T. and Heinrich, P . C. (1991) Structural and functional studies on the human interleukin-6 receptor. Binding, cross-linking, internalization, and degradation of interleukin-6 by fibroblasts transfected with human interleukin-6-receptor cDNA. J. Biol. Chem. 266, 3841–3846
[5]Hashizume, M. and Mihara, M. (2009) Influence of humanized anti-IL-6R antibody, tocilizumab on the activity of soluble gp130, natural inhibitor of IL-6 signaling. Rheumatol. Int. 29, 397–401
[6]Taga, T. and Kishimoto, T. (1997) Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 15, 797–819
[7]Dillon, S. R., Sprecher, C., Hammond, A., Bilsborough, J., Rosenfeld-Franklin, M., Presnell, S. R., Haugen, H. S., Maurer, M., Harder, B., Johnston, J. et al. (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat. Immunol. 5, 752–760
[8]Pflanz, S., Hibbert, L., Mattson, J., Rosales, R., Vaisberg, E., Bazan, J. F., Phillips, J. H., McClanahan, T. K., de Waal Malefyt, R. and Kastelein, R. A. (2004) WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231
[9]Rochman, Y ., Spolski, R. and Leonard, W . J. (2009) New insights into the regulation of T cells by γcfamily cytokines. Nat. Rev. Immunol. 9, 480–490
[10]Boulanger, M. J., Chow, D. C., Brevnova, E. E. and Garcia, K. C. (2003) Hexameric structure and assembly of the interleukin IL-6/IL-6α receptor/gp130 complex. Science 300, 2101–2104
[11]Grötzinger, J., Kernebeck, T., Kallen, K. J. and Rose-John, S. (1999) IL-6 type cytokine receptor complexes: hexamer or tetramer or both? Biol. Chem. 380, 803–813
Additional infomation from UTokyo 2023
The UTokyo2023 project used gp130(IL6ST) as the receptor domain of the MESA(Modular Extracellular Sensor Architecture) system. In the process, we examined this part (BBa K4040032) using Blast and found that the nucleotide and amino acid sequences are very different from those of gp130(IL6ST), which is generally known.
The amino acid sequence encoded by this part was searched by Blast to see what kind of protein it closely resembles, and it was found to be an exact match with the gene GP130 (gene of Caviid betaherpesvirus 2). This gene, also called gp130, has a completely different conformation and function than the glycoprotein 130 described on this page.
Click here to see UTokyo2023's newly designed gp130 (IL6ST). →BBa_K4803000(gp130 extracellular domain)
Reference
Altschul, S. F., Madden, T. L., Schäffer, A. A., Zhang, J., Zhang, Z., Miller, W., & Lipman, D. J. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic acids research, 25(17), 3389–3402.
National Center for Biotechnology Information (NCBI)[Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; [1988] – [cited 2023 Oct 12]. Available from: https://www.ncbi.nlm.nih.gov/McVoy, M. A., Wang, J. B., Dittmer, D. P., Bierle, C. J., Swanson, E. C., Fernández-Alarcón, C., ... & Schleiss, M. R. (2016). Repair of a mutation disrupting the guinea pig cytomegalovirus pentameric complex acquired during fibroblast passage restores pathogenesis in immune-suppressed guinea pigs and in the context of congenital infection. Journal of virology, 90(17), 7715-7727.
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