Difference between revisions of "Part:BBa K4175002"

Revision as of 09:54, 10 October 2022

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

Assembly Compatibility:

10
INCOMPATIBLE WITH RFC[10]
Illegal PstI site found at 640
Illegal PstI site found at 674
12
INCOMPATIBLE WITH RFC[12]
Illegal PstI site found at 640
Illegal PstI site found at 674
21
COMPATIBLE WITH RFC[21]
23
INCOMPATIBLE WITH RFC[23]
Illegal PstI site found at 640
Illegal PstI site found at 674
25
INCOMPATIBLE WITH RFC[25]
Illegal PstI site found at 640
Illegal PstI site found at 674
Illegal NgoMIV site found at 192
1000
COMPATIBLE WITH RFC[1000]

Biology

Figure 1. (Kaur et al., 2020) (a) The structure of IL-6. (b) The structure of IL-6R. (c) The structure of gp130. (d)The structure of IL-6/IL-6R/gp130 heterotrimer. (e) The strucutre of hexamer.

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 the extracellular human IL-6R with Notch core domain (BBa_K4175001) and ZF_GAl4_KRAB (BBa_K2446037) (Fig 2). In another device, we joined the truncated version of extracellular human IL-6R (aa 1-309) (BBa_K4175013) with intracellular human PD-1 (aa 191-289) (BBa_K4175003) (Fig 3). For more details about these two composite parts, please visit part pages for IL-6R-Notch-Gal4KRAB (BBa_K4175010) and IL-6R-PD-1 (BBa_K4175011), respectively.

Figure 2.IL-6R-Notch-Gal4KRAB in CAR-T cells under low and high IL-6 concentration.

Figure 3.IL-6R-PD-1 in CAR-T cells under low and high IL-6 concentration.

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

@@ Line 3: / Line 3: @@
 <partinfo>BBa_K4175002 short</partinfo>
-This part is the extracellular and transmembrane domain of human interleukin-6 receptor (IL-6R).
+This part is the extracellular and transmembrane domain of human interleukin-6 receptor (IL-6R) (aa 1-386).
-<!-- Add more about the biology of this part here
+===Sequence and Features===
-===Usage and Biology===
-<!-- -->
-<span class='h3bb'>Sequence and Features</span>
 <partinfo>BBa_K4175002 SequenceAndFeatures</partinfo>
+===Biology===
+[[File:IL-6R (1).jpg.png|thumb|center|400px|<b>Figure 1.</b> (Kaur et al., 2020) (a) The structure of IL-6. (b) The structure of IL-6R. (c) The structure of gp130. (d)The structure of IL-6/IL-6R/gp130 heterotrimer. (e) The strucutre of hexamer.]]
+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 the extracellular human IL-6R with Notch core domain (<partinfo>BBa_K4175001</partinfo>) and ZF_GAl4_KRAB (<partinfo>BBa_K2446037</partinfo>) (Fig 2). In another device, we joined the truncated version of extracellular human IL-6R (aa 1-309) (<partinfo>BBa_K4175013</partinfo>) with intracellular human PD-1 (aa 191-289) (<partinfo>BBa_K4175003</partinfo>) (Fig 3). For more details about these two composite parts, please visit part pages for IL-6R-Notch-Gal4KRAB  (<partinfo>BBa_K4175010</partinfo>) and IL-6R-PD-1  (<partinfo>BBa_K4175011</partinfo>), respectively.
+[[File:IL6R-Notch-Gal4KRAB.png|thumb|center|500px|<b>Figure 2.</b>IL-6R-Notch-Gal4KRAB in CAR-T cells under low and high IL-6 concentration.]]
+[[File:IL-6R-PD1.png|thumb|center|500px|<b>Figure 3.</b>IL-6R-PD-1 in CAR-T cells under low and high IL-6 concentration.]]
+===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
 <!-- Uncomment this to enable Functional Parameter display