Jang, Hyunbum; Arce, Fernando Teran; Ramachandran, Srinivasan; Kagan, Bruce L.; Lal, Ratnesh; Nussinov, Ruth
Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs
CHEMICAL SOCIETY REVIEWS, 43:6750-6764, 2014

Aggregation of disordered amyloidogenic peptides into oligomers is the causative agent of amyloid-related diseases. In solution, disordered protein states are characterized by heterogeneous ensembles. Among these, beta-rich conformers self-assemble via a conformational selection mechanism to form energetically-favored cross-beta structures, regardless of their precise sequences. These disordered peptides can also penetrate the membrane, and electrophysiological data indicate that they form ion-conducting channels. Based on these and additional data, including imaging and molecular dynamics simulations of a range of amyloid peptides, Alzheimer's amyloid-beta (A beta) peptide, its disease-related variants with point mutations and N-terminal truncated species, other amyloidogenic peptides, as well as a cytolytic peptide and a synthetic gel-forming peptide, we suggest that disordered amyloidogenic peptides can also present a common motif in the membrane. The motif consists of curved, moon-like beta-rich oligomers associated into annular organizations. The motif is favored in the lipid bilayer since it permits hydrophobic side chains to face and interact with the membrane and the charged/polar residues to face the solvated channel pores. Such channels are toxic since their pores allow uncontrolled leakage of ions into/out of the cell, destabilizing cellular ionic homeostasis. Here we detail A beta, whose aggregation is associated with Alzheimer's disease (AD) and for which there are the most abundant data. AD is a protein misfolding disease characterized by a build-up of A beta peptide as senile plaques, neurodegeneration, and memory loss. Excessively produced A beta peptides may directly induce cellular toxicity, even without the involvement of membrane receptors through A beta peptide-plasma membrane interactions.

DOI:10.1039/c3cs60459d

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