Elucidating the molecular, structural and supramolecular basis of 33-mer gliadin oligomers and their role in gluten-related disorders

• Applicant: Dr. Veronica Isabel Dodero Bendana
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 430578458

The 33-mer gliadin peptide is a key player in the context of gluten-related disorders, a group of immunological disorders with a high prevalence in Western societies (1-7%). This 33-mer amino acid is the product of the incomplete proteolysis of gliadins present in wheat gluten and it possesses the gluten-immunodominant sequence that triggers autoimmunity in susceptible individuals. Nevertheless, the molecular events triggering gluten-related disorders have not been described yet. We showed that the α-gliadin mixtures and the 33-mer gliadin peptide are able to form soluble oligomers and superstructures under physiological conditions. Importantly, we discovered that the 33-mer peptide suffers a structural transition towards a parallel β-sheet structure during the self-assembly process. Oligomerisation and a parallel beta-sheet structure formation are the hallmarks of amyloidosis. Moreover, we demonstrated that the 33-mer superstructures activate the innate immune response in macrophages mediated by Toll-like Receptors (TLRs). In this sense, our working hypothesis is that the accumulation and aggregation of the 33-mer peptide could be an unknown and key factor which triggers the disease. Therefore, the aim of this project is to elucidate the molecular, structural and supramolecular basis of 33-mer oligomerization and the behaviour of the 33-mer nanostructures in their interaction and transport in gut epithelial cell models. This multidisciplinary project combines different methodologies including peptide chemistry, structural and supramolecular characterisation, cellular biology approaches, proteomics and super-resolution optical microscopy. The combination of these methodologies is the win-win strategy to quantify and understand the role of the 33-mer oligomers and superstructures as triggers of the disease. Our findings will open new avenues in the understanding of gluten-related disorders directed towards the design of new effective treatments beyond the gluten-free diet.

• DFG Programme: Research Grants