# IL4R

## Overview
The IL4R gene encodes the interleukin 4 receptor alpha (IL-4Rα), a type I transmembrane protein that plays a pivotal role in the immune system by mediating the actions of the cytokine interleukin-4 (IL-4). This receptor is crucial for the regulation of immune responses, particularly in the development and differentiation of T helper 2 (Th2) cells, which are essential for humoral immunity and allergic responses. IL-4Rα is a component of both type I and type II IL-4 receptors, interacting with various cytokines and forming complexes that initiate critical signaling pathways such as the Jak-Stat pathway. These interactions are vital for the modulation of immune responses and have significant implications in inflammation and allergic reactions (Bankaitis2015Targeting; Nelms1999THE). The receptor's structure includes characteristic cytokine receptor motifs and undergoes post-translational modifications that are essential for its function and interaction with IL-4 (Gessner2000Biologic; Schulte1997Molecular).

## Structure
The IL4R protein, encoded by the IL4R gene, is a member of the cytokine receptor family and plays a crucial role in the immune response by serving as a receptor for interleukin 4. The molecular structure of IL4R includes a glycosylated transmembrane protein with a molecular weight of approximately 140 kD. It features an extracellular domain characterized by two cysteine pairs and a WSXWS motif, typical of type I cytokine receptors (Gessner2000Biologic; Schulte1997Molecular). This domain also contains two fibronectin type III (fnIII) domains, each comprising about 100 residues linked by a connector region, which are crucial for ligand binding (Naz2019Characterization).

The IL4R protein can exist in both membrane-bound and soluble forms, the latter produced through alternative splicing, which results in a 40 kD protein that retains the ability to bind IL-4 with high affinity (Schulte1997Molecular). The receptor's interaction with IL-4 involves significant charge complementarity, which is essential for the high-affinity protein-protein interactions (Naz2019Characterization).

Post-translational modifications of IL4R include glycosylation, which is significant for its function and structure. Notably, a specific amino acid substitution in the extracellular domain can lead to the loss of an N-glycosylation site, significantly affecting the receptor's IL-4 neutralizing activity (Schulte1997Molecular). The receptor complex typically comprises the IL-4Rα and the common gamma chain (γc), which associate with kinases essential for initiating signal transduction (Nelms1999THE).

## Function
The IL4R gene encodes the interleukin 4 receptor alpha (IL-4Rα), which is essential for the IL-4 mediated signaling pathways in immune system regulation. IL-4Rα is a component of both type I and type II IL-4 receptors, playing a pivotal role in mediating the biological functions of the interleukin-4 cytokine. The type I receptor, primarily expressed by hematopoietic cells, includes the IL4Rα and common gamma C (γc) subunits, crucial for the development and function of Th2 T lymphocytes and B cells. The type II receptor, expressed also by non-hematopoietic cells, consists of the IL4Rα and IL13Rα1 subunits, indicating a broader role in immune response and inflammation (Bankaitis2015Targeting).

IL-4Rα is involved in several critical signaling pathways that regulate immune responses and cell survival. It plays a crucial role in protecting cells from apoptosis and is central to the Jak-Stat signaling pathway. This pathway is particularly important for the activation of Stat-6, which upon activation, translocates to the nucleus to activate gene transcription, critical for immune response modulation (Nelms1999THE).

Furthermore, IL-4Rα's interaction with IL-4 is vital for the differentiation of naive helper T cells into Th2 cells, which are essential for humoral immunity and producing antibodies necessary for effective immune responses against pathogens and in allergic reactions (Bankaitis2015Targeting).

## Clinical Significance
Mutations and polymorphisms in the IL4R gene, which encodes the alpha chain of the interleukin 4 receptor, have been associated with various autoimmune and inflammatory diseases. Notably, the I50V and Q551R polymorphisms have been studied for their potential associations with asthma and rheumatoid arthritis (RA). The Q551R polymorphism, in particular, has been linked to an increased risk of asthma, especially in Asian populations and children, and is significantly associated with atopic asthma (Nie2013Association). Conversely, the I50V polymorphism has been suggested as a risk factor for RA, although findings have been inconsistent across studies (Peng2013Associations).

Additionally, the IL4R gene has been implicated in atopic conditions through its role in immune response modulation. A specific gain-of-function mutation, R576, enhances receptor signaling capabilities, leading to higher expression levels of CD23 by interleukin-4 and is prevalent among patients with allergic inflammatory disorders such as the hyper-IgE syndrome and severe atopic dermatitis (Hershey1997The).

These genetic variations in IL4R affect the immune system's function and are crucial for understanding the susceptibility and progression of related diseases. The study of these associations helps in identifying potential therapeutic targets and improving the management of these conditions.

## Interactions
The IL4R protein, encoded by the IL4R gene, primarily interacts with the cytokine interleukin-4 (IL-4). This interaction is facilitated by the structural arrangement of IL4R, which includes two fibronectin-III type domains connected by a linker region, forming a binding site for IL-4. The binding involves a four-helix complex in an anti-parallel arrangement with two elongated loops linked by a short beta-sheet structure, characterized by charge complementarity between key residues of IL-4 and IL4R alpha (Naz2019Characterization).

IL4R also forms complexes with other cytokine receptors. For instance, upon binding IL-4, IL4R can engage with either IL-2Rg or IL-13Ra1 to form type I or type II receptor complexes, respectively. These complexes are crucial for downstream signaling, which involves Janus kinases (JAKs) associated with the cytoplasmic tails of the receptors (Weidemann2011Single). Additionally, IL4R interacts with the common gamma chain (gc), which is shared among various cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21), and mutations in gc affect its interaction with these cytokines differently (Mueller2002Structure). 

Moreover, IL4R also interacts with IL-13 through the IL-13R1 subunit, forming a complex that significantly increases binding affinity when both subunits are engaged (Kraich2006A). This interaction showcases the modular architecture of IL4R, allowing for scalable affinity while maintaining high specificity, crucial for the distinct yet overlapping biological functions of IL-4 and IL-13 in immune response and allergic inflammation (Kraich2006A).


## References


[1. (Hershey1997The) Gurjit K. Khurana Hershey, Michal F. Friedrich, Laura A. Esswein, Matthew L. Thomas, and Talal A. Chatila. The association of atopy with a gain-of-function mutation in the α subunit of the interleukin-4 receptor. New England Journal of Medicine, 337(24):1720–1725, December 1997. URL: http://dx.doi.org/10.1056/nejm199712113372403, doi:10.1056/nejm199712113372403. (578 citations) 10.1056/nejm199712113372403](https://doi.org/10.1056/nejm199712113372403)

[2. (Schulte1997Molecular) T. Schulte, R. Kurrle, M. Röllinghoff, and A. Gessner. Molecular characterization and functional analysis of murine interleukin 4 receptor allotypes. The Journal of Experimental Medicine, 186(9):1419–1429, November 1997. URL: http://dx.doi.org/10.1084/jem.186.9.1419, doi:10.1084/jem.186.9.1419. (31 citations) 10.1084/jem.186.9.1419](https://doi.org/10.1084/jem.186.9.1419)

[3. (Nie2013Association) Wei Nie, Yuansheng Zang, Jiquan Chen, and Qingyu Xiu. Association between interleukin-4 receptor α chain (il4ra) i50v and q551r polymorphisms and asthma risk: an update meta-analysis. PLoS ONE, 8(7):e69120, July 2013. URL: http://dx.doi.org/10.1371/journal.pone.0069120, doi:10.1371/journal.pone.0069120. (15 citations) 10.1371/journal.pone.0069120](https://doi.org/10.1371/journal.pone.0069120)

[4. (Weidemann2011Single) Thomas Weidemann, Remigiusz Worch, Kristina Kurgonaite, Martin Hintersteiner, Christian Bökel, and Petra Schwille. Single cell analysis of ligand binding and complex formation of interleukin-4 receptor subunits. Biophysical Journal, 101(10):2360–2369, November 2011. URL: http://dx.doi.org/10.1016/j.bpj.2011.10.014, doi:10.1016/j.bpj.2011.10.014. (45 citations) 10.1016/j.bpj.2011.10.014](https://doi.org/10.1016/j.bpj.2011.10.014)

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[10. (Kraich2006A) Michael Kraich, Markus Klein, Edwin Patiño, Henning Harrer, Joachim Nickel, Walter Sebald, and Thomas D Mueller. A modular interface of il-4 allows for scalable affinity without affecting specificity for the il-4 receptor. BMC Biology, April 2006. URL: http://dx.doi.org/10.1186/1741-7007-4-13, doi:10.1186/1741-7007-4-13. (78 citations) 10.1186/1741-7007-4-13](https://doi.org/10.1186/1741-7007-4-13)

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