title: Small-Anion Selective Transmembrane "Holes" Induced by an Antimicrobial Peptide Too Short to Span Membranes.
abstract: Whereas many membrane-destabilization modes have been suggested for membrane-spanning antimicrobial peptides (AMPs), few are available for those too short to span membrane thickness. Here we show that ORB-1, a 15-residue disulfide-bridged AMP that is only ∼20 Å long even when fully stretched like a hairpin, may act by inducing small anion-selective transmembrane "holes" of negative mean curvature. In model membranes of Gram-negative bacteria, ORB-1 induces chloride transmembrane transport and formation of transmembrane channels of negative mean curvature, whereas the inactive analogue, ORB-N, does not, suggesting a correlation between antibacterial activity and ability to induce transmembrane channels. Given that ORB-N is the C-terminus amidated form of ORB-1, our results further suggest that formation of membrane-spanning dimers may be required to initiate the observed channel induction. Moreover, ORB-1 renders model bacterial membranes permeable to anions with effective hydration diameters of <1 nm (e.g., Cl(-) and NO3(-)), but not cations of similar sizes (e.g., H3O(+)), indicative of anion-selective transmembrane channels with an effective inner diameter of ≤1 nm. In addition, negative-intrinsic-curvature (NIC) lipids such as phosphoethanolamine (PE) may facilitate the membrane-destabilization process of ORB-1. Our findings may expand current understandings on how AMPs destabilize membranes and facilitate the pharmaceutical development of ORB-1.
authors.forename: Kan
authors.initials: K
authors.lastname: Hu
authors.forename: Yunjiang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Xie
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: ‡Biotoxin Units of Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: ‡Biotoxin Units of Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
mesh_terms: D000838:Anions / Q000737:chemistry / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006461:Hemolysis; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D017136:Ion Transport; D008954:Models, Biological; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D000838:Anions; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D007473:Ion Channels; D010714:Phosphatidylethanolamines; D010715:Phosphatidylglycerols; D053835:Unilamellar Liposomes; C094877:dioleoyl phosphatidylethanolamine; C051388:1,2-dioleoyl-sn-glycero-3-phosphoglycerol