Common mechanism unites membrane poration by amyloid and antimicrobial peptides

Abstract

Poration of bacterial membranes by antimicrobial peptides such as magainin 2 is a significant activity performed by innate immune systems. Pore formation by soluble forms of amyloid proteins such as islet amyloid polypeptide (IAPP) is implicated in cell death in amyloidoses. Similarities in structure and poration activity of these two systems suggest a commonality of mechanism. Here, we investigate and compare the mechanisms by which these peptides induce membrane leakage and bacterial cell death through the measurement of liposome leakage kinetics and bacterial growth inhibition. For both systems, leakage occurs through the nucleation-dependent formation of stable membrane pores. Remarkably, we observe IAPP and magainin 2 to be fully cross-cooperative in the induction of leakage and inhibition of bacterial growth. The effects are dramatic, with mixtures of these peptides showing activities >100-fold greater than simple sums of the activities of individual peptides. Direct protein-protein interactions cannot be the origin of cooperativity, as IAPP and its enantiomer D-IAPP are equally cross-cooperative. We conclude that IAPP and magainin 2 induce membrane leakage and cytotoxicity through a shared, cross-cooperative, tension-induced poration mechanism.amylin | diabetes | lipid biophysics | membrane protein folding | toxic oligomer

Utilisation of the isobole methodology to study dietary peptide–drug and peptide–peptide interactive effects on dipeptidyl peptidase IV (DPP-IV) inhibition

“…However, the Sitagliptin:Trp-Pro (1:852) mixture showed an antagonistic effect on DPP-IV inhibition. The extent of apparent IC 50 increase 20 compared to Zt was 9 % for the Sitagliptin:Trp-Pro (1:852) mixture. In the case of the Sitagliptin:Ile-Pro-Ile-Gln-Tyr (1:426 and 1:852) mixtures, a synergistic effect was seen with a reduction of the IC 50 value compared to Zt of 7 and 11 %, respectively.…”

“…This indicates that the overall DPP-IV inhibitory effect seen in food protein hydrolysates originates from a mixture of peptides rather than a single peptide. The isobole methodology has been mainly utilised to study interactive effects between 75 drugs, fertilisers, pesticides and phytochemicals 13 with a limited number of examples applied to antimicrobial peptide mixtures 20,21 . An additive effect of Sitagliptin (when studied at one level) and peptide mixtures on DPP-IV inhibitory properties has previously been shown 11 .…”

“…15 The antagonistic activity of peptide mixtures on DPP-IV inhibition could result in the activity of specific peptides being "masked" by the presence of other peptides. This may have consequences in particular in bioassay driven fractionation approaches where specific fractions may be erroneously 20 disregarded even though they contain relatively potent DPP-IV inhibitory peptides. Similar results have been described where the immunomodulatory properties of an hydrolysate was less than that of its associated isoelectric focusing fractions when tested at the same concentration 26 .…”

Process of inducing pores in membranes by melittin

“…It is important to differentiate between these three types of phenomena. In particular, it is well established that the minimal inhibitory concentration values of melittin and other antimicrobial peptides are in the micromolar range (6,7,19,20). A close correlation between the formation of stable pores and the antimicrobial activities was recently shown by Last and Miranker (20).…”

Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

“…A recent study by Last and Miranker proposes that IAPP and magainin 2 form membrane pores through a common mechanism [128]. However, it should be noted that the membrane pores induced by IAPP and antimicrobial peptides may be quite different in structure.…”