Structure of Foot-and-mouth disease virus serotype A1061 alone and complexed with oligosaccharide receptor: receptor conservation in the face of antigenic variation

Abstract

Foot-and-mouth disease viruses (FMDVs) target epithelial cells via integrin receptors, but can acquire the capacity to bind cell-surface heparan sulphate (or alternative receptors) on passage in cell culture. Vaccine viruses must be propagated in cell culture and, hence, some rationale for the selection of variants in this process is important. Crystal structures are available for type O, A and C viruses and also for a complex of type O strain O 1 BFS with heparin. The structure of FMDV A10 61 (a cell culture-adapted strain) complexed with heparin has now been determined. This virus has an RGSD motif in place of the otherwise conserved RGD integrin-binding motif and the potential to bind heparan sulphate (suggested by sequence analyses). FMDV A10 61 was closely similar in structure to other serotypes, deviating most in antigenic sites. The VP1 GH loop comprising the integrin-binding motif was disordered. Heparin bound at a similar site and in a similar conformation to that seen in the analogous complex with O 1 BFS, although the binding had a lower affinity and was more ionic.

Heparan Sulfate-Binding Foot-and-Mouth Disease Virus Enters Cells via Caveola-Mediated Endocytosis

“…Finally, it was demonstrated that some FMDV serotypes, when adapted to tissue culture, gain the ability to utilize cell surface heparan sulfate (HS) as a viral receptor (2, 35, 45, 54), resulting in the attenuation of virulence in host species (70). The interactions between these virions and HS have recently been delineated by crystallographic analyses (19,(27)(28)(29). These data, along with recent evidence that FMDV interaction with soluble ␣ V ␤ 6 integrin does not result in structural alterations to the virion (22), suggest that the viral receptor plays a role only in docking and internalizing the virion.…”

Positively Charged Residues at the Five-Fold Symmetry Axis of Cell Culture-Adapted Foot-and-Mouth Disease Virus Permit Novel Receptor Interactions

“…The integrin-binding loop of FMDV A/Turkey/2/2006 includes the sequence RGDLGPL, and therefore the KGD viruses could use ␣v␤6 due to the presence of the DLGPL sequence. Other viable FMDVs have been described with mutations in the RGD (28,52,53), and some of these retain the D of the RGD motif and the conserved residues normally found after the RGD (see the introduction). For most of these viruses, integrin binding has not been investigated; however, a type A virus described by Rieder et al (52) with SGD was shown to preferentially infect cells transfected to express ␣v␤6, implying that this integrin may be used as a receptor.…”

“…For example, cell culture growth often selects for viruses that use heparan sulfate (HS) as a receptor; HS can initiate infection via an integrin-independent process (26)(27)(28)(29)(30)(31)(32)(33). As a result, cell culture-adapted viruses have an increased virulence and expanded host range for cultured cells.…”

Recombinant VP1 protein of duck hepatitis virus 1 expressed in Pichia pastoris and its immunogenicity in ducks

“…The RGD-recognizing α v β 3 integrin is known as the vitronectin receptor. The mutation of the RGD motif into SGD or RGSD would affect the interaction of the virion with the cellular receptor (Fry et al, 2005;Rieder et al, 2005). In this study, we did not find the consensus sequence RGD in the VP1 of the DHV-1 VJ09 isolate.…”