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Issue 40, 2019
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Molecular mechanisms of 33-mer gliadin peptide oligomerisation

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Abstract

The proteolytic resistant 33-mer gliadin peptide is an immunodominant fragment in gluten and responsible for the celiac disease and other gluten-related disorders. Meanwhile, the primary structure of the 33-mer is associated with the adaptive immune response in celiac patients, and the structural transformation of the 33-mer into protofilaments activates a primordial innate immune response in human macrophages. This means that accumulation, oligomerisation and structural transformation of the 33-mer could be the unknown first event that triggers the disease. Herein, we reveal the early stepwise mechanism of 33-mer oligomerisation by combining multiple computational simulations, tyrosine cross-linking, fluorescence spectroscopy and circular dichroism experiments. Our theoretical findings demonstrated that the partial charge distribution along the 33-mer molecule and the presence of glutamine that favours H-bonds between the oligomers are the driving forces that trigger oligomerisation. The high content of proline is critical for the formation of the flexible PPII secondary structure that led to a β structure transition upon oligomerisation. Experimentally, we stabilised the 33-mer small oligomers by dityrosine cross-linking, detecting from dimers to higher molecular weight oligomers, which confirmed our simulations. The relevance of 33-mer oligomers as a trigger of the disease as well as its inhibition may be a novel therapeutic strategy for the treatment of gluten-related disorders.

Graphical abstract: Molecular mechanisms of 33-mer gliadin peptide oligomerisation

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Publication details

The article was received on 25 Apr 2019, accepted on 23 Sep 2019 and first published on 23 Sep 2019


Article type: Paper
DOI: 10.1039/C9CP02338K
Phys. Chem. Chem. Phys., 2019,21, 22539-22552

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    Molecular mechanisms of 33-mer gliadin peptide oligomerisation

    M. J. Amundarain, M. G. Herrera, F. Zamarreño, J. F. Viso, M. D. Costabel and V. I. Dodero, Phys. Chem. Chem. Phys., 2019, 21, 22539
    DOI: 10.1039/C9CP02338K

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