Assembly Pathways of Islet Amyloid Polypeptide (IAPP) and Aggregation Inhibition with IAPP-GI

摘要

Aggregation of Islet Amyloid Polypeptide (hIAPP) has been identified as an important pathogenic process in Type II Diabetes, a disease affecting more than 150 million people world wide. hIAPP is a peptide that is produced and stored along with insulin in the secretory granules of the pancreatic beta-cells. While atomistic characterization of the hIAPP fibril structures has been emerging, small oligomeric assemblies of hIAPP have been recently identified as the primary cytotoxic species responsible for beta-cell death in the pancreas. However, due to the transient nature of the hIAPP aggregation process, the structural details of the monomer and oligomers remain elusive. Ion mobility spectrometry combined with mass spectrometry (IMS-MS) and all-atom Replica Exchange Molecular Dynamics (REMD) simulations have been used to characterize the structures of hIAPP and the non-aggregating and non-toxic rat form of IAPP (rIAPP). Based on these studies an aggregation mechanism has been proposed which includes a pathway for IAPP assembly from beta-hairpin monomers to form beta-sheet rich oligomers.