Alternative titles; symbols
HGNC Approved Gene Symbol: CXADR
Cytogenetic location: 21q21.1 Genomic coordinates (GRCh38): 21:17,513,043-17,636,262 (from NCBI)
Coxsackie B viruses (CVB) are RNA viruses of the Picornavirus family. Carson et al. (1997) used a series of protein chromatography steps to purify a protein that bound to CVB3 from HeLa cells. They determined the N-terminal peptide sequence of this protein and used BLAST searches to identify cDNAs; one of the cDNAs containing this peptide sequence was mapped to human chromosome 21q21-cen. Thus this gene is likely to be distinct from a previously described CVB susceptibility gene (120050).
Bergelson et al. (1997) used immunoaffinity chromatography to purify a coxsackievirus and adenovirus receptor protein, which they termed CAR. Based on the sequences of tryptic peptides, they cloned the corresponding cDNA from a HeLa cell library. The CAR cDNA encodes a predicted 365-amino acid polypeptide that contains a single transmembrane domain and is a member of the immunoglobulin superfamily. Bergelson et al. (1997) found that Chinese hamster cells bound to labeled coxsackie viruses B3 and B4 and became susceptible to infection when transfected with CAR cDNA.
Tomko et al. (1997) independently cloned CXADR from a HeLa cell cDNA library, using a mouse Cxadr cDNA that they had previously cloned from a mouse kidney cell library. The deduced 365-amino acid human peptide has a calculated molecular mass of 39 kD and shares 83% sequence identity with the mouse homolog. Both peptides contain a potential leader sequence, transmembrane domains, 2 N-linked glycosylation sites, and 2 extracellular disulfide-bonded loops resembling the characteristic V and C2 domains of the immunoglobulins.
By Northern blot analysis, Tomko et al. (1997) detected highest expression of 1.4-kb and 6-kb CXADR transcripts in pancreas, brain, heart, small intestine, testis, and prostate, lower expression in liver and lung, and no expression in kidney, placenta, peripheral blood leukocytes, thymus, and spleen. In comparison, mouse Cxadr showed highest expression in liver, and lower levels in kidney, heart, lung, and brain.
By Western blot analysis of transfected cells, Tomko et al. (1997) detected CXADR proteins of 46 kD and 44 kD, suggesting posttranslational modification.
Tomko et al. (1997) found that transfection of CXADR or Cxadr into NIH 3T3 cells conferred susceptibility to infection by CVB3 and CVB4, resulting in 100- to 1000-fold higher virus titers following exposure than that found in nontransfected control cultures.
Myocarditis and dilated cardiomyopathy are common causes of morbidity and mortality in children. Many studies have implicated the enteroviruses and particularly the coxsackie virus B and adenovirus receptor offers a partial explanation for the observation that 2 such divergent virus families cause these diseases (Griffin et al., 1995; Martin et al., 1994; Pauschinger et al., 1999).
Gamma-delta T cells present in epithelial tissues provide a crucial first line of defense against environmental insults, including infection, trauma, and malignancy. Witherden et al. (2010) identified an epithelial gamma-delta T cell-specific costimulator molecule, junctional adhesion molecule-like protein (JAML; 609770). Binding of JAML to its ligand CAR provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation led to diminished gamma-delta T cell activation and delayed wound closure akin to that seen in the absence of gamma-delta T cells. The results of Witherden et al. (2010) identified JAML as a crucial component of epithelial gamma-delta T cell biology and implicated CAR and JAML in tissue homeostasis and repair.
Bowles et al. (1999) determined that the CXADR gene contains 7 exons.
Crystal Structure
Verdino et al. (2010) reported crystal structures of JAML ectodomain at 2.2 angstroms and its complex with CAR at 2.8 angstroms. The structures revealed an unusual immunoglobulin domain assembly for JAML and a charged interface that confers high specificity. Biochemical and mutagenesis studies illustrated how CAR-mediated clustering of JAML recruits phosphoinositide 3-kinase (PI3K; see 171834) to a JAML intracellular sequence motif as delineated for the alpha-beta T cell costimulatory receptor CD28 (186760). Verdino et al. (2010) concluded that CAR and JAML are cell signaling receptors of the immune system with implications for asthma, cancer, and chronic nonhealing wounds.
By PCR amplification of a monochromosomal hybrid panel, Bowles et al. (1999) mapped the functional CXADR gene to chromosome 21 and CXADR pseudogenes to chromosomes 15, 18, and 21. By FISH, they regionalized the assignment of the CXADR gene to 21q11.2.
Bergelson, J. M., Cunningham, J. A., Droguett, G., Kurt-Jones, E. A., Krithivas, A., Hong, J. S., Horwitz, M. S., Crowell, R. L., Finberg, R. W. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275: 1320-1323, 1997. [PubMed: 9036860] [Full Text: https://doi.org/10.1126/science.275.5304.1320]
Bowles, K. R., Gibson, J., Wu, J., Shaffer, L. G., Towbin, J. A., Bowles, N. E. Genomic organization and chromosomal localization of the human coxsackievirus B-adenovirus receptor gene. Hum. Genet. 105: 354-359, 1999. [PubMed: 10543405] [Full Text: https://doi.org/10.1007/s004399900136]
Carson, S. D., Chapman, N. N., Tracy, S. M. Purification of the putative coxsackievirus B receptor from HeLa cells. Biochem. Biophys. Res. Commun. 233: 325-328, 1997. [PubMed: 9144533] [Full Text: https://doi.org/10.1006/bbrc.1997.6449]
Griffin, L. D., Kearney, D., Ni, J., Jaffe, R., Fricker, F. J., Webber, S., Demmler, G., Gelb, B. D., Towbin, J. A. Analysis of formalin-fixed and frozen myocardial autopsy samples for viral genome in childhood myocarditis and dilated cardiomyopathy with endocardial fibroelastosis using polymerase chain reaction (PCR). Cardiovasc. Path. 4: 3-11, 1995.
Martin, A. B., Webber, S., Fricker, F. J., Jaffe, R., Demmler, G., Kearney, D., Zhang, Y.-H., Bodurtha, J., Gelb, B., Ni, J., Bricker, J. T., Towbin, J. A. Acute myocarditis: rapid diagnosis by PCR in children. Circulation 90: 330-339, 1994. [PubMed: 8026015] [Full Text: https://doi.org/10.1161/01.cir.90.1.330]
Pauschinger, M., Bowles, N. E., Fuentes-Garcia, F. J., Pham, V., Kuhl, U., Schwimmbeck, P. L., Schultheiss, H.-P., Towbin, J. A. Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 99: 1348-1354, 1999. [PubMed: 10077520] [Full Text: https://doi.org/10.1161/01.cir.99.10.1348]
Tomko, R. P., Xu, R., Philipson, L. HCAR and MCAR: the human and mouse receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc. Nat. Acad. Sci. 94: 3352-3356, 1997. [PubMed: 9096397] [Full Text: https://doi.org/10.1073/pnas.94.7.3352]
Verdino, P., Witherden, D. A., Havran, W. L., Wilson, I. A. The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K. Science 329: 1210-1214, 2010. [PubMed: 20813955] [Full Text: https://doi.org/10.1126/science.1187996]
Witherden, D. A., Verdino, P., Rieder, S. E., Garijo, O., Mills, R. E., Teyton, L., Fischer, W. H., Wilson, I. A., Havran, W. L. The junctional adhesion molecule JAML is a costimulatory receptor for epithelial gamma-delta T cell activation. Science 329: 1205-1210, 2010. [PubMed: 20813954] [Full Text: https://doi.org/10.1126/science.1192698]