The role of the cellular membrane environment in mediating fibrillization and toxicity of islet amyloid polypeptide

Thesis

Islet amyloid polypeptide (IAPP) is a peptide that is produced by the beta cells in the pancreas. A misfolded, aggregated form of this peptide is associated with Type 2 Diabetes and is found as large brils in pancreata, intimately associated with the islet architecture. The role of these brils is though to be benign in terms of membrane damage. However, smaller oligomers that assemble en-route to becoming brils are thought to be toxic to cells. In addition, the assembly of the peptide into amyloid is known to be accelerated by lipid and the assembly process itself has been shown to cause damage to cell and articial lipid membranes. The environment in which Islet amyloid polypeptide is produced is in secretory granules that are highly regulated, and various environmental factors have been shown to aect assembly of IAPP into brils. The work presented in this thesis looks at two important factors from these granules, zinc and pH, and their eect on the interaction of this peptide with the membrane. Using lipid membrane mimetics, I have shown a novel function of membrane fusion for human IAPP and in addition show that this function can be modulated by zinc. I have also investigated the consequences for membrane at the molecular scale using environment-sensitive uorophores that report on lipid order and viscosity. Finally, I show that depending on the lipid composition and the pH, hIAPP and rIAPP can increase the order of lipid membranes.

Authors: Carmen, H

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford