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Mechanisms for the Insertion of Toxic, Fibril-like ?-Amyloid Oligomers into the Membrane.


ABSTRACT: Amyloid-? (A?) oligomers destabilize cellular ionic homeostasis, mediating Alzheimer's disease (AD). It is still unclear whether the mechanism (i) is mediated by cell surface receptors; (ii) is direct, with A? oligomers interacting with membrane lipids; or (iii) both mechanisms take place. Recent studies indicate that A? oligomers may act by either of the last two. Little is known about the oligomers' structures and how they spontaneously insert into the membrane. Using explicit solvent molecular dynamics (MD) simulations, we show that fibril-like A?(17-42) (p3) oligomer is capable of penetrating the membrane. Insertion is similar to that observed for protegrin-1 (PG-1), a cytolytic ?-sheet-rich antimicrobial peptide (AMP). Both A? and PG-1 favor the amphipathic interface of the lipid bilayer in the early stage of interaction with the membrane. U-shaped A? oligomers are observed in solution and in the membrane, suggesting that the preformed seeds can be shared by amyloid fibrils in the growth phase and membrane toxicity. Here we provide sequential events in possible A? oligomer membrane-insertion pathways. We speculate that for the U-shaped motif, a trimer is the minimal oligomer size to insert effectively. We propose that monomers and dimers may insert in (apparently on-pathway) aggregation-intermediate ?-hairpin state, and may (or may not) convert to a U-shape in the bilayer. Together with earlier observations, our results point to a non-specific, broadly heterogeneous landscape of membrane-inserting oligomer conformations, pathways, and membrane-mediated toxicity of ?-rich oligomers.

SUBMITTER: Jang H 

PROVIDER: S-EPMC3539805 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Mechanisms for the Insertion of Toxic, Fibril-like β-Amyloid Oligomers into the Membrane.

Jang Hyunbum H   Connelly Laura L   Arce Fernando Teran FT   Ramachandran Srinivasan S   Kagan Bruce L BL   Lal Ratnesh R   Nussinov Ruth R  

Journal of chemical theory and computation 20121205 1


Amyloid-β (Aβ) oligomers destabilize cellular ionic homeostasis, mediating Alzheimer's disease (AD). It is still unclear whether the mechanism (i) is mediated by cell surface receptors; (ii) is direct, with Aβ oligomers interacting with membrane lipids; or (iii) both mechanisms take place. Recent studies indicate that Aβ oligomers may act by either of the last two. Little is known about the oligomers' structures and how they spontaneously insert into the membrane. Using explicit solvent molecula  ...[more]

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