Structure of amyloid ?25-35 in lipid environment and cholesterol-dependent membrane pore formation.

ABSTRACT: The amyloid ? (A?) peptide and its shorter variants, including a highly cytotoxic A?25-35 peptide, exert their neurotoxic effect during Alzheimer's disease by various mechanisms, including cellular membrane permeabilization. The intrinsic polymorphism of A? has prevented the identification of the molecular basis of A? pore formation by direct structural methods, and computational studies have led to highly divergent pore models. Here, we have employed a set of biophysical techniques to directly monitor Ca2+-transporting A?25-35 pores in lipid membranes, to quantitatively characterize pore formation, and to identify the key structural features of the pore. Moreover, the effect of membrane cholesterol on pore formation and the structure of A?25-35 has been elucidated. The data suggest that the membrane-embedded peptide forms 6- or 8-stranded ?-barrel like structures. The 8-stranded barrels may conduct Ca2+ ions through an inner cavity, whereas the tightly packed 6-stranded barrels need to assemble into supramolecular structures to form a central pore. Cholesterol affects A?25-35 pore formation by a dual mechanism, i.e., by direct interaction with the peptide and by affecting membrane structure. Collectively, our data illuminate the molecular basis of A? membrane pore formation, which should advance both basic and clinical research on Alzheimer's disease and membrane-associated pathologies in general.

SUBMITTER: Kandel N 

PROVIDER: S-EPMC6389947 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature