Antimicrobial Peptides Share a Common Interaction Driven by Membrane Line Tension Reduction
Antimicrobial Peptides Share a Common Interaction Driven by Membrane Line Tension Reduction
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DOI：
10.1016/j.bpj.2016.10.003
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发表时间：
2016-11-15
影响因子：
3.4
通讯作者：
Lee, Ka Yee C.
中科院分区：
文献类型：
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作者：
Henderson, J. Michael;Waring, Alan J.;Lee, Ka Yee C.
抗菌肽(AMPs)是一类能中和多种病原体的宿主防御分子。它们的膜渗透行为通常被归因于形成孔；然而，随着AMP的不断发现，许多AMP还没有被表征，其确切机制仍不清楚。利用原子力显微镜，我们以前研究了猪白细胞中的阳离子腺苷原蛋白-1(PG-1)对模型膜的破坏。当PG-1与二肉豆蔻酰磷胆碱的两性离子膜孵育时，在低浓度时首先导致边缘不稳定，然后在中等浓度时导致孔洞缺陷，最后在高浓度时导致蠕虫状胶束结构。这些丰富的结构变化表明，孔道形成只是PG-1‘S膜破裂过程中的一个中间状态。这些结构的形成可以通过使用脂类和多肽的二元混合物的中间相框架来最好地理解，其中PG-1在降低界面双分子层张力方面起到了线性剂的作用。我们已经提出，AMP不是静态的造孔剂，而是具有降低促进膜转化的界面张力的共同能力。在对13种不同AMP的研究中，我们发现多肽线活性行为不是由总电荷驱动的，而是与它们采用不完美的二级结构有关。这些多肽结构通常位于膜界面附近的带电残基处，以促进变形，有利于它们进入膜。独一无二的是，数据显示，像阿拉米西星这样的桶状突起形成肽并不具有线活性，而环状毛孔和地毯活动的看似完全不同的模型实际上是相关的。我们推测，多肽结构和与膜相关的极性残基分布之间的这种相互作用总体上控制着AMP线的活性，据我们所知，这代表了一种合理设计新药的新途径。
Antimicrobial peptides (AMPs) are a class of host-defense molecules that neutralize a broad range of pathogens. Their membrane-permeabilizing behavior has been commonly attributed to the formation of pores; however, with the continuing discovery of AMPs, many are uncharacterized and their exact mechanism remains unknown. Using atomic force microscopy, we previously characterized the disruption of model membranes by protegrin-1 (PG-1), a cationic AMP from pig leukocytes. When incubated with zwitterionic membranes of dimyristoylphosphocholine, PG-1 first induced edge instability at low concentrations, then porous defects at intermediate concentrations, and finally worm-like micelle structures at high concentrations. These rich structural changes suggested that pore formation constitutes only an intermediate state along the route of PG-1's membrane disruption process. The formation of these structures could be best understood by using a mesophase framework of a binary mixture of lipids and peptides, where PG-1 acts as a line-active agent in lowering interfacial bilayer tensions. We have proposed that rather than being static pore formers, AMPs share a common ability to lower interfacial tensions that promote membrane transformations. In a study of 13 different AMPs, we found that peptide line-active behavior was not driven by the overall charge, and instead was correlated with their adoption of imperfect secondary structures. These peptide structures commonly positioned charged residues near the membrane interface to promote deformation favorable for their incorporation into the membrane. Uniquely, the data showed that barrel-stave-forming peptides such as alamethicin are not line-active, and that the seemingly disparate models of toroidal pores and carpet activity are actually related. We speculate that this interplay between peptide structure and the distribution of polar residues in relation to the membrane governs AMP line activity in general and represents a novel, to our knowledge, avenue for the rational design of new drugs.