title: Phosphatidylethanolamine binding is a conserved feature of cyclotide-membrane interactions.
abstract: Cyclotides are bioactive cyclic peptides isolated from plants that are characterized by a topologically complex structure and exceptional resistance to enzymatic or thermal degradation. With their sequence diversity, ultra-stable core structural motif, and range of bioactivities, cyclotides are regarded as a combinatorial peptide template with potential applications in drug design. The mode of action of cyclotides remains elusive, but all reported biological activities are consistent with a mechanism involving membrane interactions. In this study, a diverse set of cyclotides from the two major subfamilies, Möbius and bracelet, and an all-d mirror image form, were examined to determine their mode of action. Their lipid selectivity and membrane affinity were determined, as were their toxicities against a range of targets (red blood cells, bacteria, and HIV particles). Although they had different membrane-binding affinities, all of the tested cyclotides targeted membranes through binding to phospholipids containing phosphatidylethanolamine headgroups. Furthermore, the biological potency of the tested cyclotides broadly correlated with their ability to target and disrupt cell membranes. The finding that a broad range of cyclotides target a specific lipid suggests their categorization as a new lipid-binding protein family. Knowledge of their membrane specificity has the potential to assist in the design of novel drugs based on the cyclotide framework, perhaps allowing the targeting of peptide drugs to specific cell types.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 Queensland, Australia.
authors.forename: Sónia Troeira
authors.initials: ST
authors.lastname: Henriques
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
authors.forename: Miguel A R B
authors.initials: MA
authors.lastname: Castanho
authors.forename: Luis A
authors.initials: LA
authors.lastname: Bagatolli
authors.forename: Secondo
authors.initials: S
authors.lastname: Sonza
authors.forename: Gilda
authors.initials: G
authors.lastname: Tachedjian
authors.forename: Norelle L
authors.initials: NL
authors.lastname: Daly
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D017124:Conserved Sequence; D047169:Cyclotides / Q000737:chemistry*; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance
chemical_list: D019380:Anti-HIV Agents; D047169:Cyclotides; D008051:Lipid Bilayers; D008055:Lipids; D010455:Peptides; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine