Antimicrobial properties of amyloid peptides

Abstract

More than two dozen clinical syndromes known as amyloid diseases are characterized by the buildup of extended insoluble fibrillar deposits in tissues. These amorphous Congo red staining deposits known as amyloids exhibit a characteristic green birefringence and cross-β structure. Substantial evidence implicates oligomeric intermediates of amyloids as toxic species in the pathogenesis of these chronic disease states. A growing body of data has suggested that these toxic species form ion channels in cellular membranes causing disruption of calcium homeostasis, membrane depolarization, energy drainage, and in some cases apoptosis. Amyloid peptide channels exhibit a number of common biological properties including the universal U-shape β-strand-turn-β-strand structure, irreversible and spontaneous insertion into membranes, production of large heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition by Congo red, and channel blockade by zinc. Recent evidence has suggested that increased amounts of amyloids not only are toxic to its host target cells but also possess antimicrobial activity. Furthermore, at least one human antimicrobial peptide, protegrin-1, which kills microbes by a channel-forming mechanism, has been shown to possess the ability to form extended amyloid fibrils very similar to those of classic disease-forming amyloids. In this paper, we will review the reported antimicrobial properties of amyloids and the implications of these discoveries for our understanding of amyloid structure and function.

Figure 1

(A) Monomer conformations of Aβ_1-42 peptides with different turn at Ser26-Ile31 (conformer 1) and at Asp23-Gly 29 (conformer 2), and the starting point of MD simulation for conformer 2. (B) Monomer conformation of 18-residues PG-1 peptide and the starting points of MD simulation. Aβ_1-42 peptides have the U-shaped β-strand-turn-β-strand motif, while PG-1 is a β-hairpin with two disulfide S-S bonds. In the cartoons, hydrophobic residues are shown in white, polar residues and Gly are shown in green, positively charged residues are shown in blue, and negatively charged residues are shown in red. In PG-1, disulfide bonds are highlighted in yellow. Side-by-side comparison between the (C-F) Aβ and (G-J) PG-1channels. The simulated Aβ barrel structures with highlighted subunits for the (C) Aβ_17-42 (p3) and (D) Aβ_9-42 (N9) barrels (Taken from Jang et al.). All barrels are viewed from the top leaflet of the lipid bilayer and depicted in a cartoon representation with a transparent surface. Each subunit in the channels is colored in a different color. AFM imges of (E) p3 and (F) N9 channels show show four or five subunits, consistent with the simulated barrels (Taken from Jang et al.). Image sizes are 15×15 and 23×23 nm², respectively. The simulated PG-1 channel structures with highlighted subunits for the (G) antiparallel and (H) parallel β-sheet channels of PG-1, and (I and J) AFM imges of PG-1 ion channels with different subunit organization (Taken from Capone et al.). Permission for all reproduced figures will be obtained.

Figure 2

AFM images (A) Aβ_1-42 (Taken from Lin et al.), and (B) Aβ_1-40 and other various amyloid channels (Taken from Quist et al.), including (C) α-synuclein, (D) ABri, (E) ADan, (F) Amylin, and (G) SAA. Permission for all reproduced figures will be obtained.

Figure 3

Channel conductance measurements representing single channel currents induced by (A) Aβ_17-42 (p3) and (B) Aβ_9-42 (N9) channels (Taken from Jang et al.), and (C) PG-1 channels (Taken from Capone et al.). Permission for all reproduced figures will be obtained.