The Generation of Antimicrobial Peptide Activity: A Trade-off between Charge and Aggregation?
The Generation of Antimicrobial Peptide Activity: A Trade-off between Charge and Aggregation?
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DOI：
10.1002/anie.201103589
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发表时间：
2011-01-01
影响因子：
16.6
通讯作者：
Andreu, David
中科院分区：
文献类型：
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作者：
Torrent, Marc;Valle, Javier;Andreu, David
抗菌肽 (AMP) 是先天免疫系统效应物，在预防感染方面发挥着至关重要的作用。尽管近年来人们对其针对传染病的潜在治疗应用进行了积极的研究，[1] AMP 发挥其活性的分子机制尚未完全了解，尽管它们显然涉及膜结合和不稳定作为常见的基本步骤。 [2]众所周知，两亲结构，例如典型的 AMP magainin 和天蚕素的结构，有利于膜结合和孔形成。 [3]有趣的是，细菌素 [4] 和颞叶蛋白 [5] 等 AMP 或溶菌酶 [6] 乳铁蛋白 [7] 和嗜酸性粒细胞阳离子蛋白 [8] 等蛋白质最近被描述可形成淀粉样蛋白样结构。此外，许多淀粉样蛋白与 AMP 具有共同的膜扰动能力，例如与带负电荷的膜结合 [9] 或对液体无序结构域的偏好。 [10]例如，淀粉样蛋白形成蛋白，如朊病毒蛋白和淀粉样蛋白 b 蛋白，可以破坏磷脂双层的稳定性 [11]，甚至被描述为具有一定的抗菌活性。 [12]确实有人认为，导致脑屏障通透和萎缩的痴呆和淀粉样蛋白沉积可能是由脂多糖或先前细菌感染留下的其他碎片引起的。 [13]所有这些证据都可以用来假设淀粉样蛋白倾向和抗菌活性相关，因为易于聚集的区域可能充当了 AMP 进化衍生的模板。为了识别淀粉样蛋白和抗菌区域共有的结构特征，我们分析了淀粉样蛋白倾向区域 [14] 和 AMP 的氨基酸频率。我们的检查显示，对于 80% 的氨基酸残基，抗菌区域和淀粉样蛋白区域均存在（或不存在）的一致趋势（图-
Antimicrobial peptides (AMPs) are innate immune system effectors with a vital role in the prevention of infection. Despite being actively researched in recent years for their potential therapeutic application against infectious diseases,[1] the molecular mechanisms by which AMPs exert their activity are not fully understood, although they clearly involve membrane binding and destabilization as a common essential step.[2] It is also well known that amphipathic structures, such as those of the typical AMPs magainin and cecropin, are favored for membrane binding and pore formation.[3] Interestingly, AMPs such as bacteriocins [4] and temporins,[5] or proteins like lysozyme,[6] lactoferrin,[7] and eosinophil cationic protein,[8] have recently been described to form amyloid-like structures. In addition, many amyloid proteins share with AMPs membrane-perturbing abilities such as binding to negatively charged membranes [9] or preference for liquid disordered domains.[10] For instance, amyloid-forming proteins, such as prion protein and amyloid-b protein, can destabilize phospholipid bilayers [11] and have even been described to possess some antimicrobial activity.[12] It has indeed been suggested that dementia and amyloid deposits that induce brain-barrier permeabilization and atrophy might result from lipopolysaccharide or other debris left over from previous bacterial infection.[13] All this evidence could be used to hypothesize that amyloid propensity and antimicrobial activity are related in the sense that aggregation-prone regions may have served as templates from which AMPs were evolutionarily derived.To identify structural features common to both amyloid and antimicrobial regions, we analyzed the amino acid frequency in amyloid-prone regions [14] and AMPs. Our inspection revealed that, for 80% of amino acid residues, there is a coincident tendency to be present in (or absent from) both antimicrobial and amyloid-like regions (Fig-