Structural Analysis of the Mechanism of Adenovirus Binding to Its Human Cellular Receptor, CAR

Abstract

NOTE:The reference numbering from the original has been maintained in this citation list.

Influence of adenoviral fiber mutations on viral encapsidation, infectivity and in vivo tropism

“…The mutations are located in the AB loop (Ser408Glu) and in the DG loop (Tyr491Asp, Ala494Asp, Phe497Asp, Met498Asp, Pro499-Gly, Ala503Asp), consistent with the results recently obtained by others. 18,19,21 In addition, the modified Leu48-5Asp-fiber virus still efficiently infects cells through CAR binding ( Figure 1). Interestingly, the substitution of the same residue to a lysine (Leu485Lys) has been shown to abolish high-affinity binding of the modified protein to CAR.…”

“…As this site is located on the side of the knob monomer, these findings imply that the trimeric knob could bind to three CAR molecules independently. 18 Bewley et al, 19 by analyzing the crystal structure of the CAR-recognizing Ad12 fiber knob complexed with the D1 domain of the CAR protein, confirmed that the AB loop of the fiber plays an essential role in the interaction with the cellular receptor. Another group also confirmed, by surface plasmon resonance and Gene Therapy cell-binding competition experiments with recombinant mutated Ad fibers, that residues located in the AB and the DE loops and in ␤-strand E and F are directly or indirectly in contact with the cellular receptor.…”

“…15,16 Only recently, through sequence analysis and mutagenesis of the knob domain of the Ad5, has a conserved receptor-binding region been identified. [17][18][19][20][21] These authors demonstrated that the CARbinding site consists of residues from the AB loop, the B ␤-sheet and the DE loop, while the FG loop seems to play an indirect role in binding CAR. As this site is located on the side of the knob monomer, these findings imply that the trimeric knob could bind to three CAR molecules independently.…”

CAR is a cell–cell adhesion protein in human cancer cells and is expressionally modulated by dexamethasone, TNFα, and TGFβ

“…The first contact of adenoviruses to cell membranes is mediated by binding of the adenoviral fiber knob to CAR 11 and subsequent binding of the RGD (arg-gly-asp) motif-bearing adenoviral capsid to RGD motif-binding integrins such as integrins a5b1, avb3 and avb5. 12 Several studies tried to establish correlations between CAR or integrin expression levels and adenoviral gene transfer efficiency.…”

Efficient repetitive gene delivery to skeletal muscle using recombinant adenovirus vector containing the Coxsackievirus and adenovirus receptor cDNA

“…5,[12][13][14] When an adenovirus particle enters a target cell, two types of receptor-mediated process are involved. First, the fiber knob of the adenovirus capsid binds to the attachment receptor on the cell surface, such as a Coxsackie B and adenovirus receptor (CAR) [15][16][17][18] and a MHC class I ␣2 domain. 19 The CAR has been reported as a 46 kDa transmembrane protein and hCAR cDNA and LacZ gene.…”