A Role for Unstructured Residues in the Induction of Membrane Poration by Pre-Amyloid Assemblies of Islet Amyloid Polypeptide

Abstract

Amyloid diseases represent a diverse class of pathologies associated with unique, aggregation-prone proteins. Although association into fibrous amyloid structure represents the end state of such aggregation, it has been observed that pre-amyloid states of these proteins may act as membrane-active toxins, providing a potential mechanism for pathology. Islet Amyloid Polypeptide (IAPP), associated with Type II diabetes, has been shown to induce cell toxicity as well as membrane poration in lipid bilayer models. Although several models of membrane-bound human (hIAPP) and non-amyloidogenic rat (rIAPP) variants have been proposed, a detailed structure of the toxic state of IAPP has remained elusive. In order to obtain a better structural and mechanistic understanding of IAPP-induced membrane poration, the extent of membrane association by different sequence regions of rIAPP has been directly compared to the magnitude of membrane poration under matched conditions via modulation of the membrane lipid composition. We find that C-terminal residues previously observed to be unstructured in the membrane bound state are nevertheless required for efficient poration. Our findings support and extend a more lipocentric view of peptide-membrane interactions, based on surface and line tension, previously suggested for membrane-active, microbe-derived peptide toxins.