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Selective membrane disruption by the cyclotide kalata B7: complex ions and essential functional groups in the phosphatidylethanolamine binding pocket
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. (Ulf Goransson)ORCID iD: 0000-0001-9070-6944
Univ Oslo, Dept Mol Biosci, Box 1041, N-0316 Oslo, Norway.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. (Ulf Goransson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. (Ulf Goransson)
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2016 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1858, no 6, 1317-1327 p.Article in journal (Refereed) Published
Abstract [en]

The cyclic cystine knot plant peptides called cyclotides are active against a wide variety of organisms. This is primarily achieved through membrane binding and disruption, in part deriving from a high affinity for phosphatidylethanolamine (PE) lipids. Some cyclotides, such as kalata B7 (kB7), form complexes with divalent cations in a pocket associated with the tyrosine residue at position 15 (Tyr15). In the current work we explore the effect of cations on membrane leakage caused by cyclotides kB1, kB2 and kB7, and we identify a functional group that is essential for PE selectivity. The presence of PE-lipids in liposomes increased the membrane permeabilizing potency of the cyclotides, with the potency of kB7 increasing by as much as 740-fold. The divalent cations Mn(2+), Mg(2+) and Ca(2+) had no apparent effect on PE selectivity. However, amino acid substitutions in kB7 proved that Tyr15 is crucial for PE-selective membrane permeabilization on various liposome systems. Although the tertiary structure of kB7 was maintained, as reflected by the NMR solution structure, mutating Tyr into Ser at position 15 resulted in substantially reduced PE selectivity. Ala substitution at the same position produced a similar reduction in PE selectivity, while substitution with Phe maintained high selectivity. We conclude that the phenyl ring in Tyr15 is critical for the high PE selectivity of kB7. Our results suggest that PE-binding and divalent cation coordination occur in the same pocket without adverse effects of competitive binding for the phospholipid.

Place, publisher, year, edition, pages
2016. Vol. 1858, no 6, 1317-1327 p.
Keyword [en]
Cyclotide, Antimicrobial peptide, Membrane permeabilization, Peptide-membrane interaction, Liposome, Phosphatidylethanolamine binding
National Category
Medical and Health Sciences Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-289123DOI: 10.1016/j.bbamem.2016.02.013ISI: 000375356900026PubMedID: 26878982OAI: oai:DiVA.org:uu-289123DiVA: diva2:924747
Funder
Swedish Society of Medicine, SLS-254511Swedish Research Council, 2012-5063
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2016-10-05

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Strömstedt, Adam A.Gunasekera, SunithiGöransson, Ulf
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