Conformational flexibility in a highly mobile protein loop of foot-and-mouth disease virus: distinct structural requirements for integrin and antibody binding

• Published in: Journal of molecular biology Vol. 283; no. 2; pp. 331 - 338
• Main Authors: Feliu, J.X, Benito, A, Oliva, B, Aviles, F.X, Villaverde, A
• Format: Journal Article
• Language: English
• Published: England 23.10.1998
• Subjects: Amino Acid Sequence; Antibodies, Viral - immunology; antigen-antibody reactions; Antigens, Viral - chemistry; Antigens, Viral - immunology; Aphthovirus; Aphthovirus - chemistry; Aphthovirus - metabolism; bhk cells; binding; Capsid - chemistry; Capsid - immunology; Capsid Proteins; cell lines; coat proteins; epitopes; Foot-and-mouth disease virus A; genetic variation; hamsters; Integrins - chemistry; Integrins - immunology; kidneys; Models, Molecular; molecular conformation; Molecular Sequence Data; monoclonal antibodies; Pliability; Protein Binding; Protein Conformation; receptors; Sequence Homology, Amino Acid
• DOI: 10.1006/jmbi.1998.2104
• ISSN: 0022-2836

The G-H loop of foot-and-mouth disease virus VP1 protein is a highly mobile peptide, that extends from the capsid surface and that in native virions is invisible by X-ray crystallography. In serotype C, this segment contains a hypervariable region with several continuous, overlapping, B-cell epitopes that embrace the conserved Arg-Gly-Asp (RGD) cell attachment motif. The solvent-exposed positioning of this peptide by selective insertion into different structural frameworks of E. coli beta-galactosidase, generates a spectrum of antigenic variants which react distinctively with a panel of anti-VP1 monoclonal antibodies and exhibit different efficiencies as cell ligands. The cell attachment efficiency is much less restricted by the different positioning of the viral segment at the insertion sites. A molecular model of an inserted stretch reveals a highest flexibility of the RGD tripeptide segment compared with the flanking sequences, that could allow a proper accommodation to integrin receptors even in poorly antigenic conformations. The non-converging structural requirements for RGD-mediated integrin binding and antibody recognition, explains the dynamism of the generation of neutralisation-resistant antigenic variants in the viral quasi-species, arising from a conformational space of integrin-binding competent peptides. This might be of special relevance for foot-and-moth disease virus evolution, since unlike in other picornaviruses, the cell binding motif and the major neutralising B-cell epitopes overlap in a solvent-exposed peptide accessible to the host immune system, in a virion lacking canyons and similar hiding structures.