Decoding the Membrane Activity of the Cyclotide Kalata B1 THE IMPORTANCE OF PHOSPHATIDYLETHANOLAMINE PHOSPHOLIPIDS AND LIPID ORGANIZATION ON HEMOLYTIC AND ANTI-HIV ACTIVITIES
Decoding the Membrane Activity of the Cyclotide Kalata B1 THE IMPORTANCE OF PHOSPHATIDYLETHANOLAMINE PHOSPHOLIPIDS AND LIPID ORGANIZATION ON HEMOLYTIC AND ANTI-HIV ACTIVITIES
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DOI：
10.1074/jbc.m111.253393
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发表时间：
2011-07-08
影响因子：
4.8
通讯作者：
Craik, David J.
中科院分区：
文献类型：
--
作者：
Henriques, Sonia Troeira;Huang, Yen-Hua;Craik, David J.
环肽是一类来自植物的环肽，具有广泛的生物活性，包括杀虫、细胞毒性和抗hiv活性。在所有这些活动中，细胞膜似乎可能是环核苷酸的主要目标。然而，脂质膜在环聚糖活性中的作用机制尚不清楚。为了确定脂质组织在原型环肽、kalata B1 （kB1）和合成类似物活性中的作用，我们评估了它们的生物活性和对模型膜的亲和力。我们发现kB1的生物活性依赖于靶细胞膜的脂质组成。特别是，kB1的活性需要与含有磷脂酰乙醇胺（PE）头基的磷脂进行特异性相互作用，但会受到非特异性肽脂疏水相互作用的进一步调节，这种相互作用在筏状膜中更受欢迎。带负电荷的磷脂不支持高kB1亲和力。这种脂质选择性解释了kB1抗菌和溶血活性的趋势；它不针对细菌细胞壁，细菌细胞壁带负电荷，缺乏PE磷脂，但可以插入红细胞的膜，红细胞的PE含量低，外层有筏结构域。我们进一步表明，kB1的抗HIV活性是其靶向和破坏HIV颗粒膜的能力的结果，HIV颗粒膜是富含pe磷脂的筏状膜。
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.