Division of Structural Biology, The Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford OX3 7BN, UK.
National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Nat Commun. 2017 May 23;8:15408. doi: 10.1038/ncomms15408.
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.
口蹄疫病毒（FMDV）通过其衣壳蛋白 VP1 暴露的、抗原性的 GH 环中的保守精氨酸-甘氨酸-天冬氨酸（RGD）基序与整联蛋白受体（通常为 αvβ6）结合介导细胞进入，在组织培养适应的病毒中，通过与肝素硫酸盐（HS）相互作用获得的碱性突变也可以在没有整联蛋白的情况下发生感染；这种病毒在自然感染中是减毒的。在两种血清型中，在保守位点已经观察到 HS 相互作用，这表明存在与硫酸化糖结合的倾向。在这里，我们通过冷冻电子显微镜确定了 αvβ6 与两种组织培养适应的 FMDV 株之间的相互作用。在首选的结合模式中，整联蛋白的完全开放形式以前从未在高分辨率下看到过，通过与 RGD 基序和下游疏水性残基的相互作用与延伸的 GH 环结合。此外，整联蛋白的一个 N-连接糖与先前鉴定的 HS 结合位点结合，这表明其具有功能作用。
