RT Journal Article
SR Electronic
T1 Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 095158
DO 10.1101/095158
A1 Melissa Birol
A1 Sunil Kumar
A1 Elizabeth Rhoades
A1 Andrew D. Miranker
YR 2017
UL http://biorxiv.org/content/early/2017/02/23/095158.abstract
AB Peptide mediated gain-of-toxic function is central to pathology in Alzheimer’s, Parkinson’s 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.HighlightsThe peptide amyloid precursor, IAPP, forms two classes of membrane porating oligomers.The two classes have a >100-fold difference in pore size with the large pore form correlated with mitochondrial depolarization and toxicity.A drug-like molecule distinguishes between the two oligomer classes and rescues toxicity by stabilizing non-toxic poration without displacing IAPP from the mitochondria.The mechanism of pore-forming oligomer assembly includes stepwise coalescence of smaller, dynamic assemblies.