| Autor: |
Amundarain MJ; Grupo de Biofísica, Instituto de Física del Sur, Universidad Nacional del Sur, Bahía Blanca, Buenos Aires, Argentina. costabel@criba.edu.ar., Herrera MG, Zamarreño F, Viso JF, Costabel MD, Dodero VI |
| Jazyk: |
angličtina |
| Zdroj: |
Physical chemistry chemical physics : PCCP [Phys Chem Chem Phys] 2019 Oct 16; Vol. 21 (40), pp. 22539-22552. |
| DOI: |
10.1039/c9cp02338k |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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