Selective membrane disruption by the cyclotide kalata B7: complex ions and essential functional groups in the phosphatidylethanolamine binding pocket

Biochimica Et Biophysica Acta
Adam A StrömstedtUlf Göransson

Abstract

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 sele...Continue Reading

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Citations

May 18, 2016·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·D I AnderssonJ Z Kubicek-Sutherland
Jan 14, 2017·Biochemistry·Sónia Troeira Henriques, David J Craik
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Dec 27, 2019·The Journal of Organic Chemistry·Zhenguang Zhao, Norman Metanis
Dec 7, 2021·Journal of Peptide Science : an Official Publication of the European Peptide Society·Kabuzi R MbuayamaAnabella R M Gaspar

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