# CD3E

## Overview
The CD3E gene encodes the CD3 epsilon (ε) subunit, a critical component of the T-cell receptor (TCR) complex, which is essential for the immune response. This gene is located on chromosome 11 and plays a pivotal role in T-cell activation and signal transduction. The CD3ε protein is a transmembrane protein that forms part of the CD3 complex, which includes other subunits such as CD3γ, CD3δ, and CD3ζ. These subunits associate with the TCRαβ subunits to form a functional TCR complex. The CD3ε subunit contains an immunoreceptor tyrosine-based activation motif (ITAM), which is crucial for initiating signaling cascades upon antigen recognition. This signaling is vital for T-cell development, differentiation, and activation, making CD3E indispensable for adaptive immunity (Alcover2018Cell; Takeuchi2008Structural). Additionally, CD3E is involved in the assembly and surface expression of the TCR complex, ensuring proper immune function and response (Alcover2018Cell).

## Structure
The CD3E protein is a critical component of the T-cell receptor (TCR) complex, playing a significant role in T-cell activation. The primary structure of CD3E consists of a specific sequence of amino acids, including an N-terminal extracellular domain, a transmembrane region, and a cytoplasmic domain. The extracellular domain is Ig-like, contributing to the protein's ability to interact with other TCR components (Kim2000Heterodimeric).

The secondary structure of CD3E includes alpha helices and beta sheets, which are typical of immunoglobulin-like domains. The tertiary structure forms a stable three-dimensional conformation necessary for its function within the TCR complex (Kim2000Heterodimeric).

In terms of quaternary structure, CD3E interacts with other CD3 subunits, such as CD3γ and CD3δ, forming heterodimers essential for TCR assembly and signal transduction. These interactions are mediated by charged amino acids in the transmembrane domains, which are crucial for the stability and function of the TCR/CD3 complex (Kim2000Heterodimeric).

CD3E undergoes post-translational modifications, including phosphorylation, which are vital for its role in signal transduction. These modifications influence the protein's function and its interactions within the TCR complex (Bello2009Nterminal).

## Function
The CD3E gene encodes the CD3ε subunit, a critical component of the T-cell receptor (TCR) complex, which is essential for T-cell activation and signal transduction. CD3ε is part of the CD3 complex, which includes CD3γ, CD3δ, and CD3ζ subunits, and is associated with the TCRαβ subunits. This complex is crucial for recognizing antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs) (Alcover2018Cell).

CD3ε contains an immunoreceptor tyrosine-based activation motif (ITAM), which is phosphorylated upon TCR engagement with peptide-MHC complexes. This phosphorylation event facilitates the recruitment of signaling molecules such as ZAP70, initiating downstream signaling pathways that lead to T-cell activation (Takeuchi2008Structural). The CD3ε subunit is also involved in the assembly and expression of the TCR-CD3 complex at the plasma membrane, playing a dominant role in the retention and stability of these complexes within the endoplasmic reticulum until they are properly assembled (Alcover2018Cell).

The interaction between CD3ε and the adaptor protein Nck is proposed to regulate TCR surface expression and ITAM phosphorylation, potentially serving as a negative regulator by preventing erroneous T-cell activation (Takeuchi2008Structural). This interaction is crucial for maintaining the balance of T-cell activation and preventing autoimmunity.

## Clinical Significance
Mutations in the CD3E gene are associated with severe combined immunodeficiency (SCID), a condition characterized by a profound defect in both cellular and humoral immunity. Patients with CD3E mutations often present with symptoms such as pneumonia, oral candidiasis, and acute respiratory distress due to the absence or dysfunction of T cells (Setia2021Novel; Fuehrer2014Successful). A specific case involved a homozygous splice site mutation in the CD3E gene, leading to the loss of the CD3ε protein and resulting in SCID. This patient required hematopoietic stem cell transplantation to restore some immune function, although they later developed humoral immunodeficiency (Fuehrer2014Successful).

CD3E has also been implicated in autoimmune diseases. A genome-wide association study identified CD3E as a potential risk gene for celiac disease, suggesting that variants in this gene may contribute to autoimmune pathogenesis by affecting T-cell receptor signaling and immune regulation (Mansour2022GenomeWide). The Ala157Val variant in CD3E, for instance, was found to destabilize protein structure, potentially impacting immune function and contributing to disease mechanisms (Mansour2022GenomeWide).

## Interactions
CD3E is a component of the T-cell receptor (TCR) complex and plays a crucial role in T-cell activation and signaling. It interacts with other CD3 subunits, including CD3D, CD3G, and CD3Z, forming heterodimers such as CD3D/CD3E and CD3G/CD3E, which are essential for TCR assembly and function (Lu2021Malignant). CD3E is involved in the internalization and down-regulation of the TCR-CD3 complex, which is critical for modulating T-cell responses (Lu2021Malignant).

CD3E also interacts with signaling molecules like ZAP-70, a protein tyrosine kinase. The tandem SH2 domains of ZAP-70 specifically bind to the tyrosine-phosphorylated CD3E and TCR zeta chains in activated T cells, highlighting the importance of phosphotyrosine residues in these interactions (Wange1993Tandem). This interaction is crucial for the activation of downstream signaling pathways following TCR engagement (Wange1993Tandem).

In the context of cancer, CD3E expression is linked to immune cell activities and is associated with various signaling pathways, including the T cell receptor signaling pathway, which plays a role in immune evasion and the shaping of an immunosuppressive microenvironment in tumors such as low-grade glioma (Lu2021Malignant).


## References


[1. (Bello2009Nterminal) Raquel Bello, Maria Jose Feito, Gloria Ojeda, Pilar Portolés, and Jose M. Rojo. N-terminal negatively charged residues in cd3ɛ chains as a phylogenetically conserved trait potentially yielding isoforms with different isoelectric points: analysis of human cd3ɛ chains. Immunology Letters, 126(1–2):8–15, September 2009. URL: http://dx.doi.org/10.1016/j.imlet.2009.07.004, doi:10.1016/j.imlet.2009.07.004. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.imlet.2009.07.004)

[2. (Alcover2018Cell) Andrés Alcover, Balbino Alarcón, and Vincenzo Di Bartolo. Cell biology of t cell receptor expression and regulation. Annual Review of Immunology, 36(1):103–125, April 2018. URL: http://dx.doi.org/10.1146/annurev-immunol-042617-053429, doi:10.1146/annurev-immunol-042617-053429. This article has 250 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1146/annurev-immunol-042617-053429)

[3. (Mansour2022GenomeWide) Haifa Mansour, Babajan Banaganapalli, Khalidah Khalid Nasser, Jumana Yousuf Al-Aama, Noor Ahmad Shaik, Omar Ibrahim Saadah, and Ramu Elango. Genome-wide association study-guided exome rare variant burden analysis identifies il1r1 and cd3e as potential autoimmunity risk genes for celiac disease. Frontiers in Pediatrics, February 2022. URL: http://dx.doi.org/10.3389/fped.2022.837957, doi:10.3389/fped.2022.837957. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fped.2022.837957)

[4. (Setia2021Novel) Priyanka Setia, Umair Ahmed Bargir, Jahnavi Aluri, Abhilasha Sampagar, Anand Pandit, Vinay Kumar, Neha Jodhawat, Snehal Shabrish, Sneha Sawant, Madhura Kelkar, Priyanka Kambli, Aparna Dalvi, and Manisha Madkaikar. Novel cd3z and cd3e deficiency in two unrelated females. Journal of Clinical Immunology, 41(5):1116–1118, March 2021. URL: http://dx.doi.org/10.1007/s10875-021-01010-w, doi:10.1007/s10875-021-01010-w. This article has 0 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s10875-021-01010-w)

[5. (Takeuchi2008Structural) Koh Takeuchi, Hailin Yang, Elise Ng, Sungh-youk Park, Zhen-Yu J. Sun, Ellis L. Reinherz, and Gerhard Wagner. Structural and functional evidence that nck interaction with cd3ε regulates t-cell receptor activity. Journal of Molecular Biology, 380(4):704–716, July 2008. URL: http://dx.doi.org/10.1016/j.jmb.2008.05.037, doi:10.1016/j.jmb.2008.05.037. This article has 40 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2008.05.037)

[6. (Wange1993Tandem) R.L. Wange, S.N. Malek, S Desiderio, and L.E. Samelson. Tandem sh2 domains of zap-70 bind to t cell antigen receptor zeta and cd3 epsilon from activated jurkat t cells. Journal of Biological Chemistry, 268(26):19797–19801, September 1993. URL: http://dx.doi.org/10.1016/s0021-9258(19)36584-6, doi:10.1016/s0021-9258(19)36584-6. This article has 205 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0021-9258(19)36584-6)

[7. (Lu2021Malignant) Xiuqin Lu, Chuanyu Li, Wenhao Xu, Yuanyuan Wu, Jian Wang, Shuxian Chen, Hailiang Zhang, Huadong Huang, Haineng Huang, and Wangrui Liu. Malignant tumor purity reveals the driven and prognostic role of cd3e in low-grade glioma microenvironment. Frontiers in Oncology, September 2021. URL: http://dx.doi.org/10.3389/fonc.2021.676124, doi:10.3389/fonc.2021.676124. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2021.676124)

[8. (Kim2000Heterodimeric) Ki Seok Kim, Zhen-Yu J Sun, Gerhard Wagner, and Ellis L Reinherz. Heterodimeric cd3ϵγ extracellular domain fragments: production, purification and structural analysis. Journal of Molecular Biology, 302(4):899–916, September 2000. URL: http://dx.doi.org/10.1006/jmbi.2000.4098, doi:10.1006/jmbi.2000.4098. This article has 14 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1006/jmbi.2000.4098)

[9. (Fuehrer2014Successful) M. Fuehrer, U. Pannicke, C. Schuetz, E.-M. Jacobsen, A. Schulz, W. Friedrich, K. Schwarz, and M. Hönig. Successful haploidentical hematopoietic stem cell transplantation in a patient with scid due to cd3ε deficiency: need for igg-substitution 6 years later. Klinische Pädiatrie, 226(03):149–153, February 2014. URL: http://dx.doi.org/10.1055/s-0033-1361142, doi:10.1055/s-0033-1361142. This article has 5 citations.](https://doi.org/10.1055/s-0033-1361142)