Difference between revisions of "Part:BBa K4160001"

 
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EpoR is a type I cytokine receptor that initiates signal transduction when its ligand binds. The GEMS receptor is based on a mutated form of the EpoR, that is inert to erythropoietin
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<p>The erythropoietin receptor (EpoR) is a type I cytokine receptor. This receptor induces downstream signaling after binding of its ligand erythropoietin (Epo).<sup>1</sup> The EpoR forms the foundation of the Generalized Extraceullar Molecule Sensor (GEMS) receptor that was developed by Schneller et al., 2018.<sup>2</sup> This part encodes for an EpoR construct that has been designed to develop the GEMS receptor. This construct is a truncated form of the EpoR that has been mutated to render it inert to Epo.<sup>2</sup></p><br>
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===Usage and Biology===
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<span class='h3bb'>Sequence and Features</span>
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<span class='h3bb'><h3>Sequence and Features</h3></span>
 
<partinfo>BBa_K4160001 SequenceAndFeatures</partinfo>
 
<partinfo>BBa_K4160001 SequenceAndFeatures</partinfo>
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<h2>Usage and Biology</h2>
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<p>The erythropoietin receptor (EpoR) is a type I cytokine receptor,<sup>1</sup> that originates from <i>Homo sapiens (Human)</i>.<sup>3</sup> The EpoR is predominantly expressed on the surface of immature erythroid cells.<sup>1</sup> Together with its ligand Epo, it is the primary regulator of mammalian erythropoiesis (the production of red blood cells).<sup>4</sup> Binding of Epo to the EpoR induces proliferation, survival, and differentiation of erythroid progenitors into red blood cells.<sup>1,4</sup><br>
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When EpoR is in its inactive form, the EpoR dimers are locked by transmembrane helix interactions. This conformation prevents downstream signaling.<sup>2</sup> Binding of the hormone Epo induces reorientation and dimerization of two EpoR monomers, which forms an active dimeric receptor structure (Figure 1). Consequently, signal transduction via Janus Kinase 2 (JAK2) is initiated by the intracellular domains of the EpoR.<sup>1,4</sup></p><br>
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<figure><img src="https://static.igem.org/mediawiki/parts/8/8f/BBa_K4160001_TU-Eindhoven_EpoR.png" width="640px" heigth=480px">
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<p><b> Figure 1 | Activation of the erythropoietin receptor.</b> In the presence of erythropoietin, the EpoR activates through a conformational change between the two receptor subunits.</p>
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<h3>Modularity</h3>
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<p>Due to the simplicity of molecular structures and activation modes, type I cytokine receptors have been engineered intensively.<sup>5</sup> Cytokine receptors have a modular structure that permits the combination of different intracellular and extracellular domains.<sup>2</sup> Therefore, the extracellular affinity domains of cytokine receptors can be modified easily, without adjusting downstream signaling properties.<sup>5</sup> Hence, synthetic cytokine receptors are emerging as a platform to develop improved and modulated immunotherapeutic strategies.<sup>6</sup></p><br>
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<h3>GEMS receptor</h3>
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<p><a href="https://2022.igem.wiki/tu-eindhoven/">The TU-Eindhoven team 2022</a> used this part to form the robust, modular GEMS receptor (<a href="https://parts.igem.org/Part:BBa_K4160008">BBa_K4160008</a>). Different synthetic receptors were developed by fusing several affinity domains to the N-terminus of the EpoR. In addition, the intracellular transduction domain IL-6RB (<a href="https://parts.igem.org/Part:BBa_K4160002">BBa_K4160002</a>) was fused C-terminal transmembrane domain of the EpoR. Due to its modularity, the EpoR provides a valuable platform for studies in synthetic biology and for the development of cell-based therapies.<sup>2</sup> Hence, this part, which other iGEM teams can use effortlessly, has much potential for therapeutics.</p><br>
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<h2>Characterization</h2>
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<p>Characterization of the EpoR incorporated in the GEMS receptor can be found on the <a href="https://parts.igem.org/Part:BBa_K4160008">BBa_K4160008</a> page.</p><br><br>
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<h2>References</h2>
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<li>Watowich SS. The Erythropoietin Receptor. J Investig Med. 2011;59(7):1067-1072. doi:10.2310/JIM.0B013E31820FB28C</li>
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<li>Scheller L, Strittmatter T, Fuchs D, Bojar D, Fussenegger M. Generalized extracellular molecule sensor platform for programming cellular behavior. Nat Chem Biol. Published online 2018. doi:10.1038/s41589-018-0046-z</li>
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<li>EPOR - Erythropoietin receptor - Homo sapiens (Human) | UniProtKB | UniProt. Accessed October 10, 2022. https://www.uniprot.org/uniprotkb/P19235/entry</li>
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<li>Seubert N, Royer Y, Staerk J, et al. Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor Dimer. Mol Cell. 2003;12(5):1239-1250. doi:10.1016/S1097-2765(03)00389-7</li>
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<li>Kawahara M, Nagamune T. Engineering of mammalian cell membrane proteins. Curr Opin Chem Eng. 2012;1(4):411-417. doi:10.1016/J.COCHE.2012.05.002</li>
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<li>Scheller J, Engelowski E, Moll JM, Floss DM. Immunoreceptor Engineering and Synthetic Cytokine Signaling for Therapeutics. Trends Immunol. 2019;40:258-272. doi:10.1016/j.it.2019.01.001</li>
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</small></p><br><br>
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Latest revision as of 14:13, 11 October 2022


EpoR (erythropoietin receptor)

The erythropoietin receptor (EpoR) is a type I cytokine receptor. This receptor induces downstream signaling after binding of its ligand erythropoietin (Epo).1 The EpoR forms the foundation of the Generalized Extraceullar Molecule Sensor (GEMS) receptor that was developed by Schneller et al., 2018.2 This part encodes for an EpoR construct that has been designed to develop the GEMS receptor. This construct is a truncated form of the EpoR that has been mutated to render it inert to Epo.2


Sequence and Features


Assembly Compatibility:
  • 10
    INCOMPATIBLE WITH RFC[10]
    Illegal PstI site found at 289
  • 12
    INCOMPATIBLE WITH RFC[12]
    Illegal NheI site found at 658
    Illegal PstI site found at 289
  • 21
    INCOMPATIBLE WITH RFC[21]
    Illegal XhoI site found at 172
  • 23
    INCOMPATIBLE WITH RFC[23]
    Illegal PstI site found at 289
  • 25
    INCOMPATIBLE WITH RFC[25]
    Illegal PstI site found at 289
  • 1000
    COMPATIBLE WITH RFC[1000]


Usage and Biology

The erythropoietin receptor (EpoR) is a type I cytokine receptor,1 that originates from Homo sapiens (Human).3 The EpoR is predominantly expressed on the surface of immature erythroid cells.1 Together with its ligand Epo, it is the primary regulator of mammalian erythropoiesis (the production of red blood cells).4 Binding of Epo to the EpoR induces proliferation, survival, and differentiation of erythroid progenitors into red blood cells.1,4
When EpoR is in its inactive form, the EpoR dimers are locked by transmembrane helix interactions. This conformation prevents downstream signaling.2 Binding of the hormone Epo induces reorientation and dimerization of two EpoR monomers, which forms an active dimeric receptor structure (Figure 1). Consequently, signal transduction via Janus Kinase 2 (JAK2) is initiated by the intracellular domains of the EpoR.1,4


Figure 1 | Activation of the erythropoietin receptor. In the presence of erythropoietin, the EpoR activates through a conformational change between the two receptor subunits.


Modularity

Due to the simplicity of molecular structures and activation modes, type I cytokine receptors have been engineered intensively.5 Cytokine receptors have a modular structure that permits the combination of different intracellular and extracellular domains.2 Therefore, the extracellular affinity domains of cytokine receptors can be modified easily, without adjusting downstream signaling properties.5 Hence, synthetic cytokine receptors are emerging as a platform to develop improved and modulated immunotherapeutic strategies.6


GEMS receptor

The TU-Eindhoven team 2022 used this part to form the robust, modular GEMS receptor (BBa_K4160008). Different synthetic receptors were developed by fusing several affinity domains to the N-terminus of the EpoR. In addition, the intracellular transduction domain IL-6RB (BBa_K4160002) was fused C-terminal transmembrane domain of the EpoR. Due to its modularity, the EpoR provides a valuable platform for studies in synthetic biology and for the development of cell-based therapies.2 Hence, this part, which other iGEM teams can use effortlessly, has much potential for therapeutics.


Characterization

Characterization of the EpoR incorporated in the GEMS receptor can be found on the BBa_K4160008 page.



References

  1. Watowich SS. The Erythropoietin Receptor. J Investig Med. 2011;59(7):1067-1072. doi:10.2310/JIM.0B013E31820FB28C
  2. Scheller L, Strittmatter T, Fuchs D, Bojar D, Fussenegger M. Generalized extracellular molecule sensor platform for programming cellular behavior. Nat Chem Biol. Published online 2018. doi:10.1038/s41589-018-0046-z
  3. EPOR - Erythropoietin receptor - Homo sapiens (Human) | UniProtKB | UniProt. Accessed October 10, 2022. https://www.uniprot.org/uniprotkb/P19235/entry
  4. Seubert N, Royer Y, Staerk J, et al. Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor Dimer. Mol Cell. 2003;12(5):1239-1250. doi:10.1016/S1097-2765(03)00389-7
  5. Kawahara M, Nagamune T. Engineering of mammalian cell membrane proteins. Curr Opin Chem Eng. 2012;1(4):411-417. doi:10.1016/J.COCHE.2012.05.002
  6. Scheller J, Engelowski E, Moll JM, Floss DM. Immunoreceptor Engineering and Synthetic Cytokine Signaling for Therapeutics. Trends Immunol. 2019;40:258-272. doi:10.1016/j.it.2019.01.001