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

Henriques, Sónia Troeira, Huang, Yen-Hua, Rosengren, K. Johan, Franquelim, Henri G., Carvalho, Filomena A., Johnson, Adam, Sonza, Secondo, Tachedjian, Gilda, Castanho, Miguel A. R. B., Daly, Norelle L. and Craik, David J. (2011) Decoding the membrane activity of the cyclotide kalata B1: The importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities. Journal of Biological Chemistry, 286 27: 24231-24241. doi:10.1074/jbc.M111.253393

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Author Henriques, Sónia Troeira
Huang, Yen-Hua
Rosengren, K. Johan
Franquelim, Henri G.
Carvalho, Filomena A.
Johnson, Adam
Sonza, Secondo
Tachedjian, Gilda
Castanho, Miguel A. R. B.
Daly, Norelle L.
Craik, David J.
Title Decoding the membrane activity of the cyclotide kalata B1: The importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2011-07-08
Sub-type Article (original research)
DOI 10.1074/jbc.M111.253393
Open Access Status File (Publisher version)
Volume 286
Issue 27
Start page 24231
End page 24241
Total pages 11
Place of publication Bethesda, MD, U.S.A.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted 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.
Keyword Gram-negative bacteria
Cyclic-cystine-knot
Surface-plasmon resonance
Antimicrobial peptides
Escherichia-coli
Scanning mutagenesis
Macrocyclic peptides
Molecular-mechanism
Oldenlandia-affinis
Biological-activity
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 61 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 14 Oct 2011, 03:08:43 EST by Professor David Craik on behalf of Institute for Molecular Bioscience