Molecular Mimicry - Structural Mimicry

Structural Mimicry

Despite no obvious amino acid sequence similarity from pathogen to host factors, structural studies have revealed that mimicry can still occur at the host level. In some cases, pathogenic mimics can possess a structural architecture that differs markedly from that of the functional homologues. Therefore, proteins of dissimilar sequence may have a common structure which elicits an autoimmune response. It has been hypothesized that these virulent proteins display their mimicry through molecular surfaces that mimic host protein surfaces (protein fold or three-dimensional conformation), which have been obtained by convergent evolution. It has also been theorized that these similar protein folds have been obtained by horizontal gene transfer, most likely from a eukaryotic host. This further supports the theory that microbial organisms have evolved a mechanism of concealment similar to that of higher organisms such as the African praying mantis or chameleon who camouflage themselves so that they can mimic their background as not to be recognized by others.

Despite dissimilar sequence homology between self and foreign peptide, weak electrostatic interactions between foreign peptide and the MHC can also mimic self peptide to elicit an autoimmune response within the host. For example, charged residues can explain the enhanced on-rate and reduced off-rate of a particular antigen or can contribute to a higher affinity and activity for a particular antigen that can perhaps mimic that of the host. Similarly, prominent ridges on the floor of peptide-binding grooves can do such things as create C-terminal bulges in particular peptides that can greatly increase the interaction between foreign and self peptide on the MHC. Similarly, there has been evidence that even gross features such as acidic/basic and hydrophobic/hydrophilic interactions have allowed foreign peptides to interact with an antibody or MHC and TCR. It is now apparent that sequence similarity considerations are not sufficient when evaluating potential mimic epitopes and the underlying mechanisms of molecular mimicry. Molecular mimicry, from these examples, has therefore been shown to occur in the absence of any true sequence homology.

There has been increasing evidence for mimicking events caused not only by amino acid similarities but also in similarities in binding motifs to the MHC. Molecular mimicry is thus occurring between two recognized peptides that have similar antigenic surfaces in the absence of primary sequence homology. For example, specific single amino acid residues such as cysteine (creates di-sulfide bonds), arginine or lysine (form multiple hydrogen bonds), could be essential for T cell cross-reactivity. These single residues may be the only residues conserved between self and foreign antigen that allow the structurally similar but sequence non-specific peptides to bind to the MHC.