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 2016
UL http://biorxiv.org/content/early/2016/12/18/095158.abstract
AB Peptide mediated gain-of-toxic function is central to pathology in diseases such as Alzheimer’s and diabetes. Cytotoxicity has long been correlated with self-assembly of the peptides into membrane-associated oligomers. The relationship of such species to membrane poration and the nature of poration’s effects on toxicity remain elusive. Here, we focus on islet amyloid polypeptide (IAPP), a hormone associated with β-cell loss in diabetics. Newly developed membrane leakage and diluted-FRET methods enable structure-function inquiry to focus on large N, homooligomers. Our results not only show the coexistence of two mechanisms of poration, but reveal that only one is cytotoxic. At no point do the porating conformations of IAPP match those of aqueous prepared amyloid. Membrane associated oligomers are internally dynamic and grow in discrete steps consistent with liquid-like fusion. Toxic permeation can be localized to mitochondria using a structure specific-ligand, illuminating a strategy for small molecule development applicable to partially ordered proteins.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 oligomer assembly is consistent with a stepwise coalescence of liquid-like droplets.