Abstract
Foot-and-mouth disease virus (FMDV) mediates cell entry by attachment to an integrin receptor, generally αvβ6, via a conserved arginine–glycine–aspartic acid (RGD) motif in the exposed, antigenic, GH loop of capsid protein VP1. Infection can also occur in tissue culture adapted virus in the absence of integrin via acquired basic mutations interacting with heparin sulphate (HS); this virus is attenuated in natural infections. HS interaction has been visualized at a conserved site in two serotypes suggesting a propensity for sulfated-sugar binding. Here we determined the interaction between αvβ6 and two tissue culture adapted FMDV strains by cryo-electron microscopy. In the preferred mode of engagement, the fully open form of the integrin, hitherto unseen at high resolution, attaches to an extended GH loop via interactions with the RGD motif plus downstream hydrophobic residues. In addition, an N-linked sugar of the integrin attaches to the previously identified HS binding site, suggesting a functional role.
Highlights
Foot-and-mouth disease virus (FMDV) mediates cell entry by attachment to an integrin receptor, generally avb[6], via a conserved arginine–glycine–aspartic acid (RGD) motif in the exposed, antigenic, GH loop of capsid protein VP1
FMDV can often readily adapt to tissue culture, where infection can occur in the absence of integrin via acquired basic mutations, which interact with sulfated sugars such as heparin sulfate (HS); this virus is attenuated in natural infections and we have previously visualized, in two serotypes, heparin sulphate (HS) interaction at a conserved site suggesting that FMDV may have an underlying propensity for binding sulfated sugars[6,20,21]
Prompted by advances in cryo-electron microscopy[22] and computational methods for the analysis of flexible assemblies[23], we investigate here the interaction of recombinant avb[6] with two intact FMDV particles representative of serotype O: O PanAsia (PanAsia; for which we determined a high-resolution structure by X-ray crystallography) and O1 Manisa (O1M; whose structure was determined previously, PDB: 5AC9), both chemically inactivated (Methods)
Summary
Foot-and-mouth disease virus (FMDV) mediates cell entry by attachment to an integrin receptor, generally avb[6], via a conserved arginine–glycine–aspartic acid (RGD) motif in the exposed, antigenic, GH loop of capsid protein VP1. A prominent feature of this otherwise rather smooth capsid is an exposed flexible loop (B30 residues) on VP1, termed the GH loop This loop and the RGD motif embedded within it (residues 145–147 in the O serotype) comprise a major site of neutralization by the host humoral immune response and mediate FMDV binding integrin[8,9,10,11,12]. FMDV can often readily adapt to tissue culture, where infection can occur in the absence of integrin via acquired basic mutations (for example, H56R in VP3), which interact with sulfated sugars such as heparin sulfate (HS); this virus is attenuated in natural infections and we have previously visualized, in two serotypes, HS interaction at a conserved site suggesting that FMDV may have an underlying propensity for binding sulfated sugars[6,20,21]
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