Part:BBa_K4175002
human extracellular IL-6R
This part is the extracellular and transmembrane domain of human interleukin-6 receptor (IL-6R) (aa 1-386).
Sequence and Features
- 10INCOMPATIBLE WITH RFC[10]Illegal PstI site found at 640
Illegal PstI site found at 674 - 12INCOMPATIBLE WITH RFC[12]Illegal PstI site found at 640
Illegal PstI site found at 674 - 21COMPATIBLE WITH RFC[21]
- 23INCOMPATIBLE WITH RFC[23]Illegal PstI site found at 640
Illegal PstI site found at 674 - 25INCOMPATIBLE WITH RFC[25]Illegal PstI site found at 640
Illegal PstI site found at 674
Illegal NgoMIV site found at 192 - 1000COMPATIBLE WITH RFC[1000]
Biology
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Interleukin-6 (IL-6) is a pro-inflammatory cytokine that plays a role in chronic inflammation and auto-immune diseases when unregulated. Its receptor, IL-6R (also known as CD126), consists of three domains in the extracellular part, D1, D2, and D3. The D1 is Immunoglobulin-like domain (Ig-like domain) and the D2 and D3 comprises cytokine binding domain (CBD) (Kaur et al., 2020). However, binding of IL-6 with IL-6R is not enough to transduce signals. Another receptor, gp130 (also known as CD130, or IL-6 signal transducer), is required for IL-6 signaling. This receptor consists of six extracellular domains (D1 – D6), with D1 being Ig-like domain and D2-3 being CBD (Fig 1). IL-6 first binds to IL-6R via CBD with low affinity, leading to dimer formation. Then the dimer recruits gp130 to form a heterotrimer, which has a high affinity for IL-6. Finally, this heterotrimer binds with another IL-6/IL-6R/gp130 heterotrimer to form a hexamer (Kaur et al., 2020). This hexamer can subsequently transduce signal through the long chain of gp130. The formation of the hexamer can lead to the activation of JAKs, and downstream signaling pathways such as STAT, MAPK, Erk1/2, and PI3K pathways (Garbers et al., 2012).
Usage
For our usage, we will use IL-6R as an IL-6 sensor in our negative feedback loop for CAR activity in CAR-T cells. As IL-6 plays a central role in the pathophysiology of cytokine release syndrome (CRS), the most common side effect of CAR-T therapy (Shimabukuro-Vornhagen et al., 2018), we hope this kind of feedback loop would help mitigate severe CRS. We designed two kinds of devices for this feedback loop that used IL-6R as a sensor. In the first device, we joined extracellular human IL-6R with intracellular human PD-1 (aa 191-289) (BBa_K4175003) (Fig 2). In another device, we joined the truncated version of extracellular human IL-6R (aa 1-309) (BBa_K4175013) with Notch core domain (BBa_K4175001) and ZF_GAl4_KRAB (BBa_K2446037) (Fig 3). For more details about these two composite parts, please visit part pages for IL-6R-PD-1 (BBa_K4175011) and IL-6R-Notch-Gal4KRAB (BBa_K4175010), respectively.
References
Garbers, C., Hermanns, H.M., Schaper, F., Müller-Newen, G., Grötzinger, J., Rose-John, S., Scheller, J., 2012. Plasticity and cross-talk of Interleukin 6-type cytokines. Cytokine Growth Factor Rev. 23, 85–97. https://doi.org/10.1016/j.cytogfr.2012.04.001
Kaur, S., Bansal, Y., Kumar, R., Bansal, G., 2020. A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors. Bioorg. Med. Chem. 28, 115327. https://doi.org/10.1016/j.bmc.2020.115327
Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M., Stemmler, H.J., Schlößer, H.A., Schlaak, M., Kochanek, M., Böll, B., von Bergwelt-Baildon, M.S., 2018. Cytokine release syndrome. J. Immunother. Cancer 6, 56. https://doi.org/10.1186/s40425-018-0343-9
| biology | Human |