Molecular and Structural Parallels between Gluten Pathogenic Peptides and Bacterial-Derived Proteins by Bioinformatics Analysis

DIEGO S. VAZQUEZ; HANNA M. SCHILBERT ; VERONICA I. DODERO

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Lugar: Basel; Año: 2021 vol. 22 p. 9278 - 9278

1422-0067

Gluten-related disorders (GRDs) are a group of diseases that involve the activation of theimmune system triggered by the ingestion of gluten, with a worldwide prevalence of 5%. Amongthem, Celiac disease (CeD) is a T-cell-mediated autoimmune disease causing a plethora of symptomsfrom diarrhea and malabsorption to lymphoma. Even though GRDs have been intensively studied,the environmental triggers promoting the diverse reactions to gluten proteins in susceptible individuals remain elusive. It has been proposed that pathogens could act as disease-causing environmentaltriggers of CeD by molecular mimicry mechanisms. Additionally, it could also be possible thatunrecognized molecular, structural, and physical parallels between gluten and pathogens havea relevant role. Herein, we report sequence, structural and physical similarities of the two mostrelevant gluten peptides, the 33-mer and p31-43 gliadin peptides, with bacterial pathogens usingbioinformatics going beyond the molecular mimicry hypothesis. First, a stringent BLASTp searchusing the two gliadin peptides identified high sequence similarity regions within pathogen-derivedproteins, e.g., extracellular proteins from Streptococcus pneumoniae and Granulicatella sp. Second,molecular dynamics calculations of an updated α-2-gliadin model revealed close spatial localizationand solvent-exposure of the 33-mer and p31-43 peptide, which was compared with the pathogenrelated proteins by homology models and localization predictors. We found putative functions of theidentified pathogen-derived sequence by identifying T-cell epitopes and SH3/WW-binding domains.Finally, shape and size parallels between the pathogens and the superstructures of gliadin peptidesgave rise to novel hypotheses about activation of innate immunity and dysbiosis. Based on ourstructural findings and the similarities with the bacterial pathogens, evidence emerges that thesepathologically relevant gluten-derived peptides could behave as non-replicating pathogens openingnew research questions in the interface of innate immunity, microbiome, and food research.