DIVAKARA, Madhihalli Basavaraju; MARTINEZ, Denis; RAVI, Ashwini; BHAVANA, Veer; RAMANA, Venkata; HABENSTEIN, Birgit; LOQUET, Antoine; SANTOSH, Mysore Sridhar

doi:10.1016/j.bpc.2018.12.002

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DIVAKARA, Madhihalli Basavaraju

MARTINEZ, Denis

RAVI, Ashwini

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Biophysical Chemistry. 2019, vol. 245, p. 34-40

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Misfolding of human islet amyloid polypeptide (hIAPP) into insoluble aggregates is associated with Type 2 diabetes. It has been suggested that hIAPP toxicity may be due to its accumulation in pancreatic islets, causing membrane disruption and cell permeabilization, however the molecular basis underlying its lipid association are still unclear. Here, we combine solid-state NMR, fluorescence and bright field microscopy to investigate hIAPP - lipid membrane interactions. Real-time microscopy highlights a time-dependent penetration of hIAPP oligomers toward the most buried layers of the lipid vesicles until the membrane disrupts. Deuterium NMR was conducted on liposomes at different hIAPP concentration to probe lipid internal order and thermotropism. The gel-to-fluid phase transition of the lipids is decreased by the presence of hIAPP, and site-specific analysis of the order parameter showed a significant increase of lipid order for the first eight positions of the acyl chain, suggesting a partial insertion of the peptide inside the bilayer. These results offer experimental insight into the membrane destabilization of hIAPP on model membrane vesicles.< Réduire

Mots clés en anglais

Type 2 diabetes

IAPP

ssNMR

Oligomers

Fibrillation

Membrane destabilization

Islet amyloid polypeptide

NMR spectroscopy

Lipid-protein interaction

Amyloid fibrils

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Molecular mechanisms for the destabilization of model membranes by islet amyloid polypeptide

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