title: 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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Last
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miranker
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D015169:Colony Count, Microbial; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D054806:Magainins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010231:Paracoccus denitrificans / Q000254:growth & development / Q000378:metabolism*; D010715:Phosphatidylglycerols; D013050:Spectrometry, Fluorescence
chemical_list: D000682:Amyloid; D023181:Antimicrobial Cationic Peptides; D058228:Islet Amyloid Polypeptide; D008081:Liposomes; D054806:Magainins; D010715:Phosphatidylglycerols; C051388:1,2-dioleoyl-sn-glycero-3-phosphoglycerol