Decoding the membrane activity of the cyclotide kalata B1: The importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities

Sonia Troeira Henriques, Yen-Hua Huang, Johan Rosengren, Henry Franquelim, Filomena Carvalho, Adam Johnson, Secondo Sonza, Gilda Tachedjian, Miguel A R B Castanho, Norelle Daly, David Craik

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Abstract

Cyclotides, a large family of cyclic peptides from plants, have a broad range of biological activities, including insecticidal, cytotoxic, and anti-HIV activities. In all of these activities, cell membranes seem likely to be the primary target for cyclotides. However, the mechanistic role of lipid membranes in the activity of cyclotides remains unclear. To determine the role of lipid organization in the activity of the prototypic cyclotide, kalata B1 (kB1), and synthetic analogs, their bioactivities and affinities for model membranes were evaluated. We found that the bioactivity of kB1 is dependent on the lipid composition of target cell membranes. In particular, the activity of kB1 requires specific interactions with phospholipids containing phosphatidylethanolamine (PE) headgroups but is further modulated by nonspecific peptide-lipid hydrophobic interactions, which are favored in raft-like membranes. Negatively charged phospholipids do not favor high kB1 affinity. This lipid selectivity explains trends in antimicrobial and hemolytic activities of kB1; it does not target bacterial cell walls, which are negatively charged and lacking PE-phospholipids but can insert in the membranes of red blood cells, which have a low PE content and raft domains in their outer layer. We further show that the anti-HIV activity of kB1 is the result of its ability to target and disrupt the membranes of HIV particles, which are raft-like membranes very rich in PE-phospholipids.
Original languageEnglish
Pages (from-to)24231 - 24241
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number27
DOIs
Publication statusPublished - 2011

Cite this

Henriques, Sonia Troeira ; Huang, Yen-Hua ; Rosengren, Johan ; Franquelim, Henry ; Carvalho, Filomena ; Johnson, Adam ; Sonza, Secondo ; Tachedjian, Gilda ; Castanho, Miguel A R B ; Daly, Norelle ; Craik, David. / Decoding the membrane activity of the cyclotide kalata B1: The importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 27. pp. 24231 - 24241.
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abstract = "Cyclotides, a large family of cyclic peptides from plants, have a broad range of biological activities, including insecticidal, cytotoxic, and anti-HIV activities. In all of these activities, cell membranes seem likely to be the primary target for cyclotides. However, the mechanistic role of lipid membranes in the activity of cyclotides remains unclear. To determine the role of lipid organization in the activity of the prototypic cyclotide, kalata B1 (kB1), and synthetic analogs, their bioactivities and affinities for model membranes were evaluated. We found that the bioactivity of kB1 is dependent on the lipid composition of target cell membranes. In particular, the activity of kB1 requires specific interactions with phospholipids containing phosphatidylethanolamine (PE) headgroups but is further modulated by nonspecific peptide-lipid hydrophobic interactions, which are favored in raft-like membranes. Negatively charged phospholipids do not favor high kB1 affinity. This lipid selectivity explains trends in antimicrobial and hemolytic activities of kB1; it does not target bacterial cell walls, which are negatively charged and lacking PE-phospholipids but can insert in the membranes of red blood cells, which have a low PE content and raft domains in their outer layer. We further show that the anti-HIV activity of kB1 is the result of its ability to target and disrupt the membranes of HIV particles, which are raft-like membranes very rich in PE-phospholipids.",
author = "Henriques, {Sonia Troeira} and Yen-Hua Huang and Johan Rosengren and Henry Franquelim and Filomena Carvalho and Adam Johnson and Secondo Sonza and Gilda Tachedjian and Castanho, {Miguel A R B} and Norelle Daly and David Craik",
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Decoding the membrane activity of the cyclotide kalata B1: The importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities. / Henriques, Sonia Troeira; Huang, Yen-Hua; Rosengren, Johan; Franquelim, Henry; Carvalho, Filomena; Johnson, Adam; Sonza, Secondo; Tachedjian, Gilda; Castanho, Miguel A R B; Daly, Norelle; Craik, David.

In: Journal of Biological Chemistry, Vol. 286, No. 27, 2011, p. 24231 - 24241.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Decoding the membrane activity of the cyclotide kalata B1: The importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities

AU - Henriques, Sonia Troeira

AU - Huang, Yen-Hua

AU - Rosengren, Johan

AU - Franquelim, Henry

AU - Carvalho, Filomena

AU - Johnson, Adam

AU - Sonza, Secondo

AU - Tachedjian, Gilda

AU - Castanho, Miguel A R B

AU - Daly, Norelle

AU - Craik, David

PY - 2011

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N2 - Cyclotides, a large family of cyclic peptides from plants, have a broad range of biological activities, including insecticidal, cytotoxic, and anti-HIV activities. In all of these activities, cell membranes seem likely to be the primary target for cyclotides. However, the mechanistic role of lipid membranes in the activity of cyclotides remains unclear. To determine the role of lipid organization in the activity of the prototypic cyclotide, kalata B1 (kB1), and synthetic analogs, their bioactivities and affinities for model membranes were evaluated. We found that the bioactivity of kB1 is dependent on the lipid composition of target cell membranes. In particular, the activity of kB1 requires specific interactions with phospholipids containing phosphatidylethanolamine (PE) headgroups but is further modulated by nonspecific peptide-lipid hydrophobic interactions, which are favored in raft-like membranes. Negatively charged phospholipids do not favor high kB1 affinity. This lipid selectivity explains trends in antimicrobial and hemolytic activities of kB1; it does not target bacterial cell walls, which are negatively charged and lacking PE-phospholipids but can insert in the membranes of red blood cells, which have a low PE content and raft domains in their outer layer. We further show that the anti-HIV activity of kB1 is the result of its ability to target and disrupt the membranes of HIV particles, which are raft-like membranes very rich in PE-phospholipids.

AB - Cyclotides, a large family of cyclic peptides from plants, have a broad range of biological activities, including insecticidal, cytotoxic, and anti-HIV activities. In all of these activities, cell membranes seem likely to be the primary target for cyclotides. However, the mechanistic role of lipid membranes in the activity of cyclotides remains unclear. To determine the role of lipid organization in the activity of the prototypic cyclotide, kalata B1 (kB1), and synthetic analogs, their bioactivities and affinities for model membranes were evaluated. We found that the bioactivity of kB1 is dependent on the lipid composition of target cell membranes. In particular, the activity of kB1 requires specific interactions with phospholipids containing phosphatidylethanolamine (PE) headgroups but is further modulated by nonspecific peptide-lipid hydrophobic interactions, which are favored in raft-like membranes. Negatively charged phospholipids do not favor high kB1 affinity. This lipid selectivity explains trends in antimicrobial and hemolytic activities of kB1; it does not target bacterial cell walls, which are negatively charged and lacking PE-phospholipids but can insert in the membranes of red blood cells, which have a low PE content and raft domains in their outer layer. We further show that the anti-HIV activity of kB1 is the result of its ability to target and disrupt the membranes of HIV particles, which are raft-like membranes very rich in PE-phospholipids.

UR - http://www.jbc.org/content/early/2011/05/16/jbc.M111.253393.full.pdf+html

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DO - 10.1074/jbc.M111.253393

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SP - 24231

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JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

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ER -