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 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.
Institut de Biologia Fonamental, Universitat Autònoma de Barcelona Bellaterra, 08193 Barcelona Spain.
J X
JX
Feliu
A
A
Benito
B
B
Oliva
F X
FX
Avilés
A
A
Villaverde
D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D005537:Aphthovirus / Q000737:chemistry* / Q000378:metabolism; D002213:Capsid / Q000737:chemistry* / Q000276:immunology; D036022:Capsid Proteins; D016023:Integrins / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018583:Pliability; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D016023:Integrins