Dimeric Structure of the Coxsackievirus and Adenovirus Receptor D1 Domain at 1.7 Å Resolution

Abstract

The CAR D1 domain forms homodimers in the crystal using the same GFCC'C" surface that interacts with the adenovirus fiber head. The homodimer is very similar to the CD2 D1-CD58 D1 heterodimer. CAR D1 also forms dimers in solution with a dissociation constant typical of other cell adhesion complexes. These results are consistent with reports that CAR may function physiologically as a homophilic cell adhesion molecule in the developing mouse brain. Adenovirus may thus have recruited an existing and conserved interaction surface of CAR to use for its own cell attachment.

Coxsackie and adenovirus receptor (CAR) is a product of Sertoli and germ cells in rat testes which is localized at the Sertoli–Sertoli and Sertoli–germ cell interface

“…The presence of CAR at opposing surfaces of both Sertoli and germ cells introduces the possibility that homotypical CAR interaction might take place. Structural analysis revealed that CAR form homodimer in crystal and in solution via D1 domains, the distal one of its two extracellular Ig-Like loops [31]. Interestingly, fiber knob projecting from adenovirus capsid binds to CAR through the same interface, but at a higher affinity [31,32].…”

“…Structural analysis revealed that CAR form homodimer in crystal and in solution via D1 domains, the distal one of its two extracellular Ig-Like loops [31]. Interestingly, fiber knob projecting from adenovirus capsid binds to CAR through the same interface, but at a higher affinity [31,32]. Viral fiber knob competes with CAR to interrupt cell-cell adhesions, not only for virus attachment [1,10], but also to spread viral particles from infected cells.…”

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

“…Our findings may suggest that in ovarian cancer biology soluble isoforms of CAR display an opposite function to that postulated for transmembrane hCAR. As Dorner et al found that soluble CAR proteins are able to interact with the bacterially expressed extracellular domain of hCAR 17 and the extracellular domain was shown to be critical in homodimer formation of hCAR, 36 it is tempting to speculate that CAR 4/7 and CAR 3/7 antagonize the tumor suppressive functions of hCAR via direct interaction with its extracellular domain. Insertion of soluble CAR variants into the protein network of TJs may destabilize cell-cell adhesion and significantly contribute to the detachment of single cancer cells from the primary tumor.…”

The coxsackievirus and adenovirus receptor acts as a tumour suppressor in malignant glioma cells

“…The coxsackievirus and adenovirus receptor is a 46 kDa class I membrane glycoprotein with a carboxy-terminal cytoplasmic domain, a transmembrane domain and an extracellular region consisting of two immunoglobulin-like domains, an amino-terminal immunoglobulin variable (IgV)-related domain (D1), which is distal to the cell surface, and a proximal IgC2 domain (D2). Although there is evidence for the evolutionary conservation of CAR, with homologues of the human receptor, hCAR, present in several mammalian species, including mice (Tomko et al, 1997;Bergelson et al, 1998), rats, dogs and pigs (Fechner et al, 1999) as well as in zebrafish (van Raaij et al, 2000), the normal physiological function of this membrane protein is unknown.…”