Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration

Abstract

Peptide mediated gain-of-toxic function is central to pathology in Alzheimers, Parkinsons and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here, we focus on islet amyloid polypeptide (IAPP) mediated loss of insulin secreting cells in diabetics. Newly developed methods enable structure-function inquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two class of pores coexist; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilizing non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalizable approach for inquiry applicable to other partially ordered protein assemblies.\n\nHighlightsO_LIThe peptide amyloid precursor, IAPP, forms two classes of membrane porating oligomers.\nC_LIO_LIThe two classes have a >100-fold difference in pore size with the large pore form correlated with mitochondrial depolarization and toxicity.\nC_LIO_LIA drug-like molecule distinguishes between the two oligomer classes and rescues toxicity by stabilizing non-toxic poration without displacing IAPP from the mitochondria.\nC_LIO_LIThe mechanism of pore-forming oligomer assembly includes stepwise coalescence of smaller, dynamic assemblies.\nC_LI