Structural Evaluation of a Mimicry-Recognizing Paratope: Plasticity in Antigen–Antibody Interactions Manifests in Molecular Mimicry

Abstract

Molecular mimicry manifests antagonistically with respect to the specificity of immune recognition. However, it often occurs because different Ags share surface topologies in terms of shape or chemical nature. It also occurs when a flexible paratope accommodates dissimilar Ags by adjusting structural features according to the antigenic epitopes or differential positioning in the Ag combining site. Toward deciphering the structural basis of molecular mimicry, mAb 2D10 was isolated from a maturing immune response elicited against methyl α-d-mannopyranoside and also bound equivalently to a dodecapeptide. The physicochemical evidence of this carbohydrate–peptide mimicry in the case of mAb 2D10 had been established earlier. These studies had strongly suggested direct involvement of a flexible paratope in the observed mimicry. Surprisingly, comparison of the Ag-free structure of single-chain variable fragment 2D10 with those bound to sugar and peptide Ags revealed a conformationally invariant state of the Ab while binding to chemically and structurally disparate Ags. This equivalent binding of the two dissimilar Ags was through mutually independent interactions, demonstrating functional equivalence in the absence of structural correlation. Thus, existence of a multispecific, mature Ab in the secondary immune response was evident, as was the plasticity in the interactions while accommodating topologically diverse Ags. Although our data highlight the structural basis of receptor multispecificity, they also illustrate mechanisms adopted by the immune system to neutralize the escape mutants generated during pathogenic insult.

Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody

“…The relevance of such approach was demonstrated by Pincus and collaborators (12) who demonstrated that peptides mimicking group B Streptococcus polysaccharide may provide active, protective immunization against the bacteria. However, as demonstrated here and by others (44,45) the interaction of mimetic peptides and the carbohydrate with the target antibody may differ significantly. Moreover, as demonstrated in this study, mimetic peptides characterized by different primary structure differ significantly in their interaction modes.…”

“…Two principle mechanisms were proposed by Johnson and Pinto (14): structural mimicry, whereby the peptide presents a similar arrangement of functional groups as the carbohydrate, and functional mimicry, whereby the peptide utilizes an alternative binding mode to that of the carbohydrate. Comparative analysis of a limited number of available crystal structures of antibody Fab fragments in complex with mimicking peptides and relevant carbohydrates (44,45) indicates that the actual mechanism is best described as partial structural mimicry. However, a more definitive conclusion awaits characterization of a wider variety of examples (14).…”

The Potential Roles of Bisphenol A (BPA) Pathogenesis in Autoimmunity

“…The binding of environmental BPA to host protein may lead to self-tissue, antigen-antibody interactions associated with environmentally induced molecular mimicry. Autoimmune molecular mimicry requires the similarities of surface topologies leading to antigenic combining sites [72]. The binding of BPA to PDI in host has the potential to lead to new protein epitope activation of autoimmunity (Figure 10).…”

Antibodies Can Exploit Molecular Crowding to Bind New Antigens at Noncanonical Paratope Positions

“…The overall structure exhibits standard immunoglobulin fold topology (Figure a). The structure of scFv 2D10 in disaccharide (α1‐6 mannobiose) complex superimposed well with that in the monosaccharide complex (0.36 Å RMSD) and variations in CDRs were observed in the range from 0.30‐0.77 Å implying minor rearrangements of CDR residues, mainly in CDRL1.…”

“…The α‐mannopyranoside binds to the scFv 2D10 at the centre of the antigen‐combining site . The comparison of α1‐6 mannobiose with me‐α‐D‐mannopyranoside bound scFv 2D10 structures revealed, to our surprise, that the disaccharides do not interact with the antibody where monosaccharide was observed to bind.…”