Residue specific effects of human islet amyloid polypeptide on self-assembly, on cell toxicity and on amyloid-induced membrane damage

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Amyloid fibril formation has been implicated in a wide range of human diseases and the interactions of amyloidogenic proteins with cell membranes are considered to be important in the aetiology of these pathologies. In type 2 diabetes mellitus (T2DM), the human islet amyloid polypeptide (hIAPP) forms amyloid fibrils which impair the functionality and viability of pancreatic βcells. The mechanisms of hIAPP cytotoxicity are linked to the ability of the peptide to self-aggregate and to interact with membranes. The propensity of IAPP to form amyloid fibrils is strongly dependent on its primary sequence. An intriguing example is His at residue 18. Although H18 is located outside the amyloidogenic region, it has been suggested that this residue and its charge state play an important role in the kinetics of conformational changes and fibril formation as well as in mediating cell toxicity. To gain more insight into the importance of this residue, we have synthesized four analogues (H18R-IAPP, H18K-IAPP, H18A-IAPP and H18E-IAPP) and we performed a comprehensive biophysical and biological study on the properties of these peptides using fluorescence, spectroscopy, microscopy and cell toxicity assays.



Sorbonne Université, salle 23-13-109

Mardi 29 Mai 2018 12:30
Séminaire Thématique
Unité de rattachement: 
UMR 7203
Equipe de rattachement 7203: 
Equipe 3