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). 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.

Item ID: 27027
Item Type: Article (Research - C1)
ISSN: 1083-351X
Keywords: antimicrobial peptides; antiviral agents; phosphatidylethanolamine; phospholipid vesicle; plasma membrane; cyclic peptides; hemolytic activity; cyclotides; model membranes; peptide-membrane interactions
Funders: Australian Research Council (ARC)
Projects and Grants: DP0880105
Date Deposited: 23 May 2013 02:53
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060101 Analytical Biochemistry @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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