Rules of engagement between αvβ6 integrin and foot-and-mouth disease virus

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.

The evolution of a super-swarm of foot-and-mouth disease virus in cattle

“…This VP1 S144R change arose in the background of clades I-V by way of two different codon mutations, strongly suggesting that arginine is advantageous at this position. This is also consistent with most wild-type FMDV sequences, which overwhelmingly contain arginine at this position [62]. The dynamic appearance and disappearance virus populations coupled with substitutions at the major antigenic sites suggests the existence of an antigenic selection process during long-term (persistent) infection.…”

Seneca Valley virus attachment and uncoating mediated by its receptor anthrax toxin receptor 1

“…The overall engagement is significantly different from other reported picornavirus-receptor complexes. In the FMDV-integrin and HRV2-VLDLR interactions, VP1 residues alone attach to the receptor (13,18). For PV, CV, and the major group HRVs, their receptors overlap at the canyon-like depression on the capsid, and mainly involve residues from the βC and the βE to ɑB loop of VP1 on the north rim, the GH loops of VP1 and VP3 on the floor, and the puff of VP2 on the south rim (9,11,12,15,16) of the canyon.…”

“…Several picornaviruses bind integrin receptors, usually via a flexible arginine-glycine-aspartic acid (RGD) motif. A recent cryo-EM study captured medium resolution views of the foot-andmouth disease virus (FMDV)-ɑvβ6 integrin complex and revealed the attachment via a conserved RGD motif in a very exposed and flexible VP1 GH loop (18). Notably, the complex structures reported to date have generally been determined at neutral pH (13,18).…”

Characterization of the Conjugation Pattern in Large Polysaccharide–Protein Conjugates by NMR Spectroscopy

“…Therefore, the structural characterization of the protein component, the identification of the conjugation sites, and the evaluation of the conjugation degree at different lysine sites are a compelling requirement towards structure‐based development15, 16, 17, 18 of glycoconjugate vaccines. The presence of polysaccharide chains prevents the crystallization of the protein conjugates, and extends the molecular weight of the system beyond the limits of solution NMR spectroscopy,19 similarly to what happens upon PEGylation 20, 21, 22.…”