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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.

SUBMITTER: Last NB

PROVIDER: S-EPMC3631635 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Common mechanism unites membrane poration by amyloid and antimicrobial peptides.

Last Nicholas B NB Miranker Andrew D AD

Proceedings of the National Academy of Sciences of the United States of America 20130401 16

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 deat ...[more]

PMID: 23576726

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Project description:Antimicrobial peptides (AMPs) are a class of host-defense molecules that neutralize a broad range of pathogens. Their membrane-permeabilizing behavior has been commonly attributed to the formation of pores; however, with the continuing discovery of AMPs, many are uncharacterized and their exact mechanism remains unknown. Using atomic force microscopy, we previously characterized the disruption of model membranes by protegrin-1 (PG-1), a cationic AMP from pig leukocytes. When incubated with zwitterionic membranes of dimyristoylphosphocholine, PG-1 first induced edge instability at low concentrations, then porous defects at intermediate concentrations, and finally worm-like micelle structures at high concentrations. These rich structural changes suggested that pore formation constitutes only an intermediate state along the route of PG-1's membrane disruption process. The formation of these structures could be best understood by using a mesophase framework of a binary mixture of lipids and peptides, where PG-1 acts as a line-active agent in lowering interfacial bilayer tensions. We have proposed that rather than being static pore formers, AMPs share a common ability to lower interfacial tensions that promote membrane transformations. In a study of 13 different AMPs, we found that peptide line-active behavior was not driven by the overall charge, and instead was correlated with their adoption of imperfect secondary structures. These peptide structures commonly positioned charged residues near the membrane interface to promote deformation favorable for their incorporation into the membrane. Uniquely, the data showed that barrel-stave-forming peptides such as alamethicin are not line-active, and that the seemingly disparate models of toroidal pores and carpet activity are actually related. We speculate that this interplay between peptide structure and the distribution of polar residues in relation to the membrane governs AMP line activity in general and represents a novel, to our knowledge, avenue for the rational design of new drugs.

Dataset Information

Common mechanism unites membrane poration by amyloid and antimicrobial peptides.

Publications

Common mechanism unites membrane poration by amyloid and antimicrobial peptides.

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