A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions

ABSTRACT. Polymorphisms in the CD226 gene have been reported to be associated with autoimmune diseases. The aim of our study was to investigate the association between two single nucleotide polymorphisms (SNPs) (rs763361 and rs727088) in the CD226 gene and the risk for developing type 1 diabetes (T1D) in Chinese Han children. This case-control study included a total of 152 Chinese children with T1D and 304 matchedpair, healthy controls based on age and gender. The genetic variants of the rs763361 and rs727088 SNPs in the CD226 gene were determined using the polymerase chain reaction and restriction fragment length polymorphism method. The CD226 rs763361 polymorphism increased the risk of T1D in the genotype [P < 0.001, odds ratio (OR) = 3.9, 95% confidence interval (CI) = 2.24-6.76], dominant (P < 0.001, OR = 2.1, 95%CI = 1.40-3.14), and recessive (P < 0.001, OR = 0.5, 95%CI = 0.30-0.84) models. Additionally, the carriers of the T allele were more susceptible to T1D (P < 0.001, OR = 2.1, 95%CI = 1.58-2.79). Carriers of the T allele who were younger than 10 years of age at disease onset had an increased risk of T1D than those who were older at the disease onset. However, there was no association between the CD226 rs727088 SNP and risk for developing T1D. These findings revealed that CD226 rs763361 polymorphism was significantly associated with susceptibility to T1D and that the presence of the T allele might be a genetic factor for susceptibility to T1D.

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“…+ and CD8 + T lymphocytes, natural killer cells, macrophages, and platelets (Shibuya et al, 1996;Maier and Hafler, 2009;Xu and Jin, 2010).…”

Section: Introductionmentioning

confidence: 99%

Association of CD226 polymorphisms with the susceptibility to type 1 diabetes in Chinese children

Nie

Wang

et al. 2015

Genet. Mol. Res.

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“…It has been proposed that cisduplications and translocations of this single ancestral region occurred during evolution, leading to three original complexes on three different chromosome segments: a primordial MHC that gave rise to the set of genes involved in Ag presentation; a neurotrophin complex that led to genomic regions comprising neurotrophin receptors and the Leukocyte Receptor Complex; and a third genetic complex, the tunicate MHC-related complex JAM-NECTIN (JN) that is at the origin of paralogous regions containing many Ig superfamily members. These proteins have cell adhesion properties (JAM, NECTINs, poliovirus receptors' family members) and are often implicated in the biology of lymphocytes, NK cells, and other leukocytes (CD96, cd155, cd112, JAM B, and CTX family members) (15,16,18,19). Pairs of structurally related molecules can act as receptor-ligand systems and mediate interactions between leukocytes and endothelia, linking this third proto-MHC derived complex to immunity.…”

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confidence: 99%

The Proto-MHC of Placozoans, a Region Specialized in Cellular Stress and Ubiquitination/Proteasome Pathways

Suurväli

Jouneau

Thépot

et al. 2014

The Journal of Immunology

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“…It is expressed on a variety of cells and is especially overexpressed on a variety of tumor cells (16). Nectin-2 can stimulate the reaction of NK cells and CTLs through its interaction with DNAM-1 (32).…”

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confidence: 99%

Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226

Qian

Chen

et al. 2012

The Journal of Immunology

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The nectin and nectin-like molecule (Necl) family includes important cell adhesion molecules (CAMs) characterized by their Ig-like nature. Such CAMs regulate a broad spectrum of cell–cell interactions, including the interaction between NK cells and cytotoxic T lymphocytes (CTLs) and their target cells. CAM members nectin-2 (CD112) and Necl-5 (CD155) are believed to form homodimers (for nectin-2) or heterodimers in their functions for cell adhesion, as well as to interact with immune costimulatory receptor DNAX accessory molecule 1 (DNAM-1) (CD226) to regulate functions of both NK and CTL cells. However, the structural basis of the interactive mode of DNAM-1 with nectin-2 or Necl-5 is not yet understood. In this study, a soluble nectin-2 Ig-like V-set domain (nectin-2v) was successfully prepared and demonstrated to bind to both soluble ectodomain and cell surface-expressed full-length DNAM-1. The 1.85-Å crystal structure of nectin-2v displays a perpendicular homodimer arrangement, revealing the homodimer characteristics of the nectin and Necls. Further mutational analysis indicated that disruption of the homodimeric interface of nectin-2v led to a failure of the homodimer formation, as confirmed by crystal structure and biochemical properties of the mutant protein of nectin-2v. Interestingly, the monomer mutant also loses DNAM-1 binding, as evidenced by cell staining with tetramers and surface plasmon resonance assays. The data indicate that interaction with DNAM-1 requires either the homodimerization or engagement of the homodimeric interface of nectin-2v. These results have implications for immune intervention of tumors or autoimmune diseases in the DNAM-1/nectin-2–dependent pathway.

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A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions

Cited by 82 publications

References 54 publications

Association of CD226 polymorphisms with the susceptibility to type 1 diabetes in Chinese children

Association of CD226 polymorphisms with the susceptibility to type 1 diabetes in Chinese children

The Proto-MHC of Placozoans, a Region Specialized in Cellular Stress and Ubiquitination/Proteasome Pathways

Crystal Structure of Cell Adhesion Molecule Nectin-2/CD112 and Its Binding to Immune Receptor DNAM-1/CD226

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