Gliadin proteolytical resistant peptides: the interplay between structure and self-assembly in gluten-related disorders

HERRERA MARIA GEORGINA; CHIRDO, FERNANDO GABRIEL; DODERO, VERONICA I.

Congreso; 20th IUPAB Congress, 45th Annual SBBf Meeting, and 50th Annual SBBq Meeting; 2021

Gliadin, a protein present in wheat, has become of great interest due to its role in gluten-related disorders as celiac disease and gluten sensitivity. It is known that this protein is not fully digested by humans, producing large peptides that elicit an immune response in susceptible individuals. In celiac disease, the adaptative immune response has been well characterized; however, the first inflammatory events that trigger the innate response remain elusive. Considering the relation between protein structure and function, combining different biophysical methods with cellular models is of key importance in an integrative understanding of a complex biological problem. In this context, it is hypothesized that gliadin peptides, such as the immunodominant 33-mer gliadin (LQLQPF(PQPQLPY)3PQPQPF) and the toxic p31-43 (LGQQQPFPPQQPY) could elicit an inflammatory response prior to disease due to their structural behavior. Based on that, an extensively biophysical characterization was performed in association with cellular analysis. The 33-mer peptide forms oligomers and large quaternary structures at high concentration with a Polyproline II conformation in equilibrium with parallel β-sheet secondary structure. These nanostructures activate the NFκβ pathway via TLR2 and 4, inducing the expression of proinflammatory biomarkers. The p31-43 has similar conformational behavior as the 33-mer peptide and self-organizes as oligomers and linear arrangements. These assemblies might be responsible for NLRP3 inflammasome activation in the gut, recapitulating the damage observed in patients. These results indicate that a multidisciplinary evaluation of a biological problem could help connect and reveal new pathways that were not explored in the relationship between health and