8.A.152. The Interleukin Receptor (ILR) Family
IL2R is the receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Interleukin-2 is one of the critical cytokines that controls the proliferation and differentiation of cells of the immune system. Gesbert et al. 1998 reviewed the knowledge on the intracellular signaling events that convert the initial interaction of IL-2 with its receptor into pathways leading to various biological functions. A first step in IL-2 signaling is the activation of several protein tyrosine kinases that phosphorylate an array of intracellular substrates including the receptor complex. Phosphorylated tyrosine residues within the receptor then serve as docking sites for multimolecular signaling complexes that initiate three major pathways: the Jak-STAT pathway controlling gene transcription, the Ras-MAPK pathway leading to cell proliferation and gene transcription, and the PI3-kinase pathway involved in antiapoptotic signaling and organization of the cytoskeleton (Gesbert et al. 1998). Signaling through the interleukin-4 and interleukin-13 receptor complex regulates cholangiocyte TMEM16A (1.A.17.1.1) expression and biliary secretion (Dutta et al. 2020).
The receptor for interleukin-4 (IL4) and interleukin-13 (IL13), of 825 aas and 2 TMSs, one N-terminal and one about 30% from the N-terminus, and 427 aas and 2 TMSs, one N-terminal and one C-terminal, respectively. Signaling through the interleukin-4/interleukin-13 receptor complexes regulates cholangiocyte TMEM16A (TC# 1.A.17.1.1) expression and biliary secretion (Dutta et al. 2020). The IL4/IL13 responses are involved in regulating IgE production, and chemokine and mucus production at sites of allergic inflammation. In certain cell types, it can signal through activation of insulin receptor substrates, IRS1/IRS2 (Keegan et al. 1994).
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The interleukin-2 receptor of 551 aas with 2 TMSs, one N-terminal and one in the middle of the protein (Gesbert et al. 1998). Structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4 (Spangler et al. 2015). Depolarization resulted in a decrease in the mobility of IL-2Rα and MHC glycoproteins, whereas hyperpolarization increased their mobility (Nagy et al. 2018).
IL2R of Homo sapiens
Thrombopoietin receptor isoform X2 of 616 aas and 2 TMSs, one at the N-terminus and one at about residue 430.
Thrombopoietin receptor of Denticeps clupeoides (denticle herring)
Interleukin-7 receptor, IL7R, subunit alpha; it is of 459 aas with 2 TMSs, one N-terminal, and one at about residue 250. It also acts as a receptor for thymic stromal lymphopoietin (TSLP), and may play a role in osteoporosis (Wu et al. 2023). It is found in the clathrin-coated endocytic vesicle membrane. During cotranslational translocation, the signal peptide of a nascent chain binds the Sec61 translocon to initiate protein transport through the ER membrane. The cryo-EM structure of ribosome-Sec61 shows binding of an ordered heterotetrameric translocon-associated protein (TRAP) complex, in which TRAP-gamma is anchored at two adjacent positions of 28S ribosomal RNA and interacts with ribosomal protein L38 and Sec61alpha/gamma. Four TMSs of TRAP-gamma cluster with one C-terminal helix of each alpha, beta, and delta subunit. The seven TMS bundle helps position a crescent-shaped trimeric TRAP-alpha/beta/delta core in the ER lumen, facing the Sec61 channel. A cyclotriazadisulfonamide derivative CK147 is a translocon inhibitor. A structure of ribosome-Sec61-CK147 reveals CK147 binding the channel and interacting with the plug helix from the lumenal side. The CK147 resistance mutations surround the inhibitor. These structures help in understanding TRAP functions (Pauwels et al. 2023).
IL7R of Homo sapiens
Erythropoietin receptor, EPOR, of 508 aas and two TMSs, one N-terminal and one central at about residue 260. It is a receptor for erythropoietin (EPO) that mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes, triggering the JAK2/STAT5 signaling cascade. In some cell types, it can also activate STAT1 and STAT3 as well as the LYN tyrosine kinase. The isoform EPOR-T acts as a dominant-negative receptor of EPOR-mediated signaling. It is a transmembrane type I receptor with an essential role in the proliferation and differentiation of erythroid progenitors (Tóthová et al. 2023).
EPOR of Homo sapiens
Interleukin-21 receptor-like isoform X1 of 422 aas and 3 probable TMSs, one N-terminal, one near the middle of the protein, and one near the C-terminus.
IL21-X1 of Paramormyrops kingsleyae
Interleukin 9-like receptor, isoform X1 of 517 aas and 2 TMSs, N-terminal and near the middle of the protein.
IL9-like receptor of Microcebus murinus
Erythropoietin receptor of 509 aas and 2 TMSs, one N-terminal and one near the middle of the protein.
EPR of Chinchilla lanigera
Cytokine receptor common subunit gamma-like of 354 aas and 2 TMSs.
CyR of Tauraco erythrolophus (red-crested turaco)
Interleukin 3 receptor-like protein (AIC2B) precursor of 896 aas and 2 TMSs, one N-terminal and one in the middle of the protein.
IL3R of Mus musculus
Interleukin-7 receptor subunit alphaof 465 aas and 2 TMSs, N-terminal and in the middle of the protein.
IL7R of Phalacrocorax carbo
Interleukin-21 receptor of 513 aas and 2 TMSs, one N-terminal and one in the middle of the protein.
IL21R of Ictalurus punctatus
The receptor for interleukin-4 (IL4) and interleukin-13 (IL13), of 825 aas and 2 TMSs, one N-terminal and one about 30% from the N-terminus, and 427 aas and 2 TMSs, one N-terminal and one C-terminal, respectively. Signaling through the interleukin-4/interleukin-13 receptor complexes regulates cholangiocyte TMEM16A (TC# 1.A.17.1.1) expression and biliary secretion (Dutta et al. 2020). The IL4/IL13 responses are involved in regulating IgE production, and chemokine and mucus production at sites of allergic inflammation. In certain cell types, it can signal through activation of insulin receptor substrates, IRS1/IRS2 (Keegan et al. 1994).
IL4/IL13 receptor of Homo sapiens
Ciliary neurotrophic factor receptor subunit alpha of 372 aas and 2 TMSs, N- and C-terminal. Along with intraflagellar-transport, targeted changes in sector-wise lipid composition could control receptor localisation and functions in the cilia. Dutta and Ray 2022 discussed how an interplay between ciliary lipid composition, localized lipid modification, and receptor function could contribute to cilia growth and signalling. They argue that lipid modification at the cell-cilium interface could generate an added thrust for a selective exchange of membrane lipids and the transmembrane and membrane-associated proteins.
CNTFR of Homo sapiens
Cytokine receptor-like factor 1 isoform X2, CRLF1, of 394 aas and one N-terminal TMS.
CRLF1 of Pundamilia nyererei
Prolactin receptor of 831 aas and 2 TMSs, one N-terminal and one near the middle of the protein at residue 450.
Prolactin Receptor of Gallus gallus
Interleukin-27 receptor subunit alpha isoform X2 of 831 aas and 2 TMSs, one near the N-terminus and one near the C-terminus. This protein shows sequence similarity with TC families 8.A.23 and 9.B.87.
Interleukin-27 receptor of Phascolarctos cinereus (koala)
Granulocyte colony-stimulating factor receptor isoform X1 of 801 aas and 2 TMSs, near the N- and C-termini. In front of the C-terminal TMS there are two small peaks of hydrophobicity that could be TMSs.
of Taeniopygia guttata (zebra finch)
Leptin receptor isoform X1 of 1167 aas and up to 4 TMSs at the N-terminus as well as possible TMSs at residues 300, 600, and 850.
Leptin receptor of Trachemys scripta elegans
Uncharacterized protein of 493 aas and 2 TMSs, one N-terminal and one at about residue 240.
UP of Chaenocephalus aceratus (blackfin icefish)
Prolactin receptor, PRLR, of 622 aas and two TMSs, one at the N-terminus and a second at about residue 240. The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with the phosphoinositide-4,5-bisphosphate (Araya-Secchi et al. 2023). Phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), play a crucial role in controlling key cellular functions such as membrane and vesicle trafficking, ion channel and transporter activity (Sang et al. 2024).
PRLR of Homo sapiens