Amyloid proteins: structure and dynamics

This page has been written by :
Lucie Khemtemourian

Abstract

The formation of protein amyloid deposits is associated with major human diseases including Alzheimer’s disease, Parkinson’s disease, the spongiform encephalopathy and type 2 diabetes mellitus (T2DM).

T2DM is characterized metabolically by defects in both insulin secretion and insulin action, resulting in hyperglycemia, and is histopathologically characterized by the presence of fibrillar amyloid deposits in the pancreatic islets of Langerhans (islet amyloid). The presence of these amyloid deposits in T2DM has been linked to the death of the insulin producing islet β-cells, thereby contributing to the development of this disease. Human islet amyloid polypeptide (hIAPP), a 37 amino acid peptide, is the major constituent of the amyloid deposits found in type 2 diabetic patients. IAPP and insulin are coproduced and cosecreted together by the pancreatic islet β-cells and have complementary hormone activities.

Under normal conditions, the peptide hIAPP remains soluble but, in the pancreas of T2DM patients, the increase of peptide concentration and misfolding give rise to oligomerization and to amyloid fibrils formation via a nucleation-dependent polymerization process. Unfortunately, hIAPP aggregation induces processes that impair the functionality and viability of β-cells.

The goal of our research are (i) to understand the role of membrane in hIAPP aggregation; (ii) to determine the structure of different hIAPP species; (iii) to study new molecule capable of inhibiting hIAPP fibril formation.

Methods and expertise: peptide synthesis and peptide expression; model membranes; circular dichroism; microscopy; fluorescence spectroscopy; NMR

CDNRates

Schematic representation of fibrillation of hIAPP over time

hiAPP

Negatively strained miscrosopy images of hIAPP after incubation

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