A Similar Pattern of Interaction for Different Antibodies with a Major Antigenic Site of Foot-and-Mouth Disease Virus: Implications for Intratypic Antigenic Variation

Abstract

The three-dimensional structures of the Fab fragment of a neutralizing antibody raised against a foot-and-mouth disease virus (FMDV) of serotype C1, alone and complexed to an antigenic peptide representing the major antigenic site A (G-H loop of VP1), have been determined. As previously seen in a complex of the same antigen with another antibody which recognizes a different epitope within antigenic site A, the receptor recognition motif Arg-Gly-Asp and some residues from an adjacent helix participate directly in the interaction with the complementarity-determining regions of the antibody. Remarkably, the structures of the two antibodies become more similar upon binding the peptide, and both undergo considerable induced fit to accommodate the peptide with a similar array of interactions. Furthermore, the pattern of reactivities of five additional antibodies with versions of the antigenic peptide bearing amino acid replacements suggests a similar pattern of interaction of antibodies raised against widely different antigens of serotype C. The results reinforce the occurrence of a defined antigenic structure at this mobile, exposed antigenic site and imply that intratypic antigenic variation of FMDV of serotype C is due to subtle structural differences that affect antibody recognition while preserving a functional structure for the receptor binding site.

Probing degeneracy in antigen–antibody recognition at the immunodominant site of foot‐and‐mouth disease virus

“…The involvement of Ala 138 in peptide-SD6 complexes (22) and the important role of the RGD triplet are both in agreement with previous observations (21,22,32,33). However, all mAbs were fully reactive with Thr 137 R Ile and Thr 148 R Ile replacements, which is consistent with the minimal participation of these residues in mAb-peptide interaction, as seen by X-ray diffraction studies (16,21; Ochoa et al, manuscript in preparation).…”

“…In contrast, five single point substitutions (Thr 137 → Ile, Ala 138 → Phe, Ala 140 → Pro, Gly 142 → Ser and Thr 148 → Ile) were found to preserve antigenicity towards several anti‐GH loop mAbs. Although the first and last replacements are located at each end of the loop, not in close contact with the antibody (22), the other three are at positions known to be directly involved in antibody recognition. Each of these three replacements is also remarkable because of its nonconservative character: Phe is much larger than Ala; Pro is a known disrupter of secondary structure, which Ala is not; finally, the Gly 142 → Ser mutation affects the highly conserved RGD motif.…”

“…These peptides were based on the main antigenic site of FMDV, termed site A, located on the highly flexible GH loop defined by residues 136-150 of the capsid protein VP1 in FMDV isolate C-S8c1 (19). This loop is effectively mimicked by peptide A15 (YTASARGDLAHLTTT), which has been used in several studies on antigenic structure of this viral site (13,(20)(21)(22). Site A combines hypervariable segments (137-140 148-150) with highly conserved residues such as Leu 144 and Leu 147 and, especially, the integrin-binding motif RGD, used as FMDV cell attachment site (20,21,23 Although the first and last replacements are located at each end of the loop, not in close contact with the antibody (22), the other three are at positions known to be directly involved in antibody recognition.…”

“…This loop is effectively mimicked by peptide A15 (YTASARGDLAHLTTT), which has been used in several studies on antigenic structure of this viral site (13,(20)(21)(22). Site A combines hypervariable segments (137-140 148-150) with highly conserved residues such as Leu 144 and Leu 147 and, especially, the integrin-binding motif RGD, used as FMDV cell attachment site (20,21,23 Although the first and last replacements are located at each end of the loop, not in close contact with the antibody (22), the other three are at positions known to be directly involved in antibody recognition. Each of these three replacements is also remarkable because of its nonconservative character: Phe is much larger than Ala; Pro is a known disrupter of secondary structure, which Ala is not; finally, the Gly 142 R Ser mutation affects the highly conserved RGD motif.…”

A comparative study of cyclization strategies applied to the synthesis of head‐to‐tail cyclic analogs of a viral epitope

“…On the other hand, it has been shown in a number of cases that antigenic recognition can be significantly improved by restricting peptide mobility through cyclization (6)(7)(8)(9). In our work with foot-and-mouth disease virus-related peptides, we have shown recently that a linear 15-residue sequence representing antigenic site A (A15, YTASmG-DLAHLTTT, residues 136-150 of viral protein VPi) is folded into a quasi-cyclical arrangement when it binds to the Fab fragments of neutralizing monoclonal antibodies raised against the virus (10,11). From these results it was reasonable to propose that appropriate conformational restriction of the linear pentadecapeptide might result in improved antigenic recognition.…”