CONFORMATIONAL FLEXIBILITY IN A HIGHLY MOBILE PROTEIN LOOP OF FOOT-AND-MOUTH-DISEASE VIRUS - DISTINCT STRUCTURAL REQUIREMENTS FOR INTEGRIN AND ANTIBODY-BINDING

The G-H loop of foot-and-mouth disease virus VP1 protein is a highly m obile peptide, that extends from the capsid surface and that in native virions is invisible by X-Pay crystallography, In serotype C, this se gment contains a hypervariable region with several continuous, overlap ping, B-cell epitopes that embrace the conserved Arg-Gly-Asp (RGD) cel l attachment motif. The solvent-exposed positioning of this peptide by selective insertion into different structural frameworks of E. coli b eta-galactosidase, generates a spectrum of antigenic variants which re act distinctively with a panel of anti-VP1 monoclonal antibodies and e xhibit different efficiencies as cell ligands. The cell attachment eff iciency is much less restricted by the different positioning of the vi ral segment at the insertion sites. A molecular model of an inserted s tretch reveals a highest flexibility of the RGD tripeptide segment com pared with the flanking sequences, that could allow a proper accommoda tion to integrin receptors even in poorly antigenic conformations. The non-converging structural requirements for RGD-mediated integrin bind ing and antibody recognition, explains the dynamism of the generation of neutralisation-resistant antigenic variants in the viral quasi-spec ies, arising from a conformational space of integrin-binding competent peptides. This might be of special relevance for foot-and-moth diseas e virus evolution, since unlike in other picornaviruses, the cell bind ing motif and the major neutralising B-cell epitopes overlap in a solv ent-exposed peptide accessible to the host immune system, in a virion lacking canyons and similar hiding structures. (C) 1998 Academic Press .