Lequin Olivier, Ladram Ali, Chabbert Ludovic, Bruston Francine, Convert Odile, Vanhoye Damien, Chassaing Gérard, Nicolas Pierre, Amiche Mohamed
Synthèse, structure et fonction de molécules bioactives, UMR 7613 CNRS, Université Pierre et Marie Curie, Case Courrier 45, 4 Place Jussieu, 75252 Paris Cedex 05, France.
Biochemistry. 2006 Jan 17;45(2):468-80. doi: 10.1021/bi051711i.
The dermaseptins S are closely related peptides with broad-spectrum antibacterial activity that are produced by the skin of the South American hylid frog, Phyllomedusa sauvagei. These peptides are polycationic (Lys-rich), alpha-helical, and amphipathic, with their polar/charged and apolar amino acids on opposing faces along the long axis of the helix cylinder. The amphipathic alpha-helical structure is believed to enable the peptides to interact with membrane bilayers, leading to permeation and disruption of the target cell. We have identified new members of the dermaseptin S family that do not resemble any of the naturally occurring antimicrobial peptides characterized to date. One of these peptides, designated dermaseptin S9, GLRSKIWLWVLLMIWQESNKFKKM, has a tripartite structure that includes a hydrophobic core sequence encompassing residues 6-15 (mean hydrophobicity, +4.40, determined by the Liu-Deber scale) flanked at both termini by cationic and polar residues. This structure is reminiscent of that of synthetic peptides originally designed as transmembrane mimetic models and that spontaneously become inserted into membranes [Liu, L., and Deber, C. M. (1998) Biopolymers 47, 41-62]. Dermaseptin S9 is a potent antibacterial, acting on gram-positive and gram-negative bacteria. The structure of dermaseptin S9 in aqueous solution and in TFE/water mixtures was analyzed by circular dichroism and two-dimensional NMR spectroscopy combined with molecular dynamics calculations. Dermaseptin S9 is aggregated in water, but a monomeric nonamphipathic alpha-helical conformation, mostly in residues 6-21, is stabilized by the addition of TFE. These results, combined with membrane permeabilization assays and surface plasmon resonance analysis of the peptide binding to zwitterionic and anionic phospholipid bilayers, demonstrate that spatial segregation of hydrophobic and hydrophilic/charged residues on opposing faces along the long axis of a helix is not essential for the antimicrobial activity of cationic alpha-helical peptides.
皮肤防御素S是一类密切相关的肽，具有广谱抗菌活性，由南美雨蛙（Phyllomedusa sauvagei）的皮肤产生。这些肽是聚阳离子的（富含赖氨酸）、α-螺旋的且具有两亲性，其极性/带电荷的氨基酸和非极性氨基酸沿螺旋圆柱体的长轴分布在相对的面上。据信两亲性α-螺旋结构使这些肽能够与膜双层相互作用，导致靶细胞的渗透和破坏。我们已经鉴定出皮肤防御素S家族的新成员，它们与迄今为止所表征的任何天然存在的抗菌肽均不相似。其中一种肽，命名为皮肤防御素S9，序列为GLRSKIWLWVLLMIWQESNKFKKM，具有三重结构，包括一个疏水核心序列，该序列包含6至15位残基（平均疏水性，+4.40，由Liu-Deber量表测定），在两个末端两侧均为阳离子和极性残基。这种结构让人联想到最初设计为跨膜模拟模型并能自发插入膜中的合成肽的结构[Liu, L., and Deber, C. M. (1998) Biopolymers 47, 41 - 62]。皮肤防御素S9是一种强效抗菌剂，作用于革兰氏阳性菌和革兰氏阴性菌。通过圆二色性和二维核磁共振光谱结合分子动力学计算，分析了皮肤防御素S9在水溶液和TFE/水混合物中的结构。皮肤防御素S9在水中聚集，但通过添加TFE可稳定一种单体非两亲性α-螺旋构象，主要存在于6至21位残基中。这些结果，结合膜通透性测定以及该肽与两性离子和阴离子磷脂双层结合的表面等离子体共振分析，表明沿螺旋长轴相对面上疏水和亲水/带电荷残基的空间分隔对于阳离子α-螺旋肽的抗菌活性并非必不可少。
