Cyclotides insert into lipid bilayers to form membrane pores and destabilize the membrane through hydrophobic and phosphoethanolamine-specific interactions

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dc.contributor.authorWang, CKen_AU
dc.contributor.authorWacklin, HPen_AU
dc.contributor.authorCraik, DJen_AU
dc.date.accessioned2014-04-03T23:16:24Zen_AU
dc.date.available2014-04-03T23:16:24Zen_AU
dc.date.issued2012-12-21en_AU
dc.date.statistics2014-04-04en_AU
dc.description.abstractCyclotides are a family of plant-derived circular proteins with potential therapeutic applications arising from their remarkable stability, broad sequence diversity, and range of bioactivities. Their membrane-binding activity is believed to be a critical component of their mechanism of action. Using isothermal titration calorimetry, we studied the binding of the prototypical cyclotides kalata B1 and kalata B2 (and various mutants) to dodecylphosphocholine micelles and phosphoethanolamine-containing lipid bilayers. Although binding is predominantly an entropy-driven process, suggesting that hydrophobic forces contribute significantly to cyclotide-lipid complex formation, specific binding to the phosphoethanolamine-lipid headgroup is also required, which is evident from the enthalpic changes in the free energy of binding. In addition, using a combination of dissipative quartz crystal microbalance measurements and neutron reflectometry, we elucidated the process by which cyclotides interact with bilayer membranes. Initially, a small number of cyclotides bind to the membrane surface and then insert first into the outer membrane leaflet followed by penetration through the membrane and pore formation. At higher concentrations of cyclotides, destabilization of membranes occurs. Our results provide significant mechanistic insight into how cyclotides exert their bioactivities. © 2012, American Society for Biochemistry and Molecular Biology.en_AU
dc.identifier.citationWang, C. K., Wacklin, H. P., & Craik, D. J. (2012). Cyclotides insert into lipid bilayers to form membrane pores and destabilize the membrane through hydrophobic and phosphoethanolamine-specific Interactions. Journal of Biological Chemistry, 287(52), 43884-43898. doi:10.1074/jbc.M112.421198en_AU
dc.identifier.govdoc4758en_AU
dc.identifier.issn0021-9258en_AU
dc.identifier.issue52en_AU
dc.identifier.journaltitleJournal of Biological Chemistryen_AU
dc.identifier.pagination43884-43898en_AU
dc.identifier.urihttp://dx.doi.org/10.1074/jbc.M112.421198en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/5399en_AU
dc.identifier.volume287en_AU
dc.language.isoenen_AU
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_AU
dc.subjectCystineen_AU
dc.subjectPolypeptidesen_AU
dc.subjectAIDS virusen_AU
dc.subjectProteinsen_AU
dc.subjectNeutron reflectorsen_AU
dc.subjectStructure factorsen_AU
dc.titleCyclotides insert into lipid bilayers to form membrane pores and destabilize the membrane through hydrophobic and phosphoethanolamine-specific interactionsen_AU
dc.typeJournal Articleen_AU
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