The role of the abundant phenylalanines in the mode of action of the antimicrobial peptide clavanin
The role of the abundant phenylalanines in the mode of action of the antimicrobial peptide clavanin
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DOI：
10.1016/s0005-2736(03)00233-5
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发表时间：
2003-09-02
影响因子：
3.4
通讯作者：
de Kruijff, B
中科院分区：
文献类型：
--
作者：
van Kan, EJM;Demel, RA;de Kruijff, B
克拉文素A是一种特殊的抗菌肽，通过pH依赖性机制作用于膜水平。在中性pH下，克拉维宁以非特异性方式破坏生物和模型膜，导致大分子流出。然而，在温和的酸性条件下，该肽通过透化细菌的膜而有效地杀死细菌，最有可能是通过与参与质子易位的蛋白质相互作用[Biochemistry 41（2002）7529]。克拉文素A异常富含苯丙氨酸，23个残基中有5个，这表明这些残基在功能上是重要的。一组突变体，其中所有Phe残基被替换为Ile，Leu，Trp或Tyr，用于研究这些氨基酸的作用。不同肽在中性和低pH下的抗微生物活性表明苯丙氨酸的存在不是必需的也不是最佳的，因为Tip、Leu和Ile突变体与野生型组分相比具有相同或更高的活性。一般而言，在中性pH下，生物活性与肽与膜脂质相互作用的能力良好相关。相应地，发现各种衍生物的生物膜和模型膜的透化效率与它们采用α-螺旋结构的能力密切相关，并且遵循5L> 5 W>5I> 5 Y>野生型的顺序。结果表明，Phe残基在以平衡的方式提供具有足够疏水性和膜亲和力以及构象灵活性的肽中具有重要作用。(C)2003 Elsevier B. V.保留所有权利。
Clavanin A is a special antimicrobial peptide that acts at the level of the membrane via a pH-dependent mechanism. At neutral pH, clavanin disrupts biological and model membranes in a nonspecific manner, causing efflux of large molecules. At mildly acidic conditions, however, the peptide efficiently kills bacteria by permeabilizing their membrane most likely by interacting with proteins involved in proton translocation [Biochemistry 41 (2002) 7529]. Clavanin A is unusually rich in phenylalanines with 5 out of 23 residues, which suggests that these residues are functionally important. A set of mutants, in which all Phe residues are replaced by either Ile, Leu, Trp, or Tyr was used to investigate the role of these amino acids. The antimicrobial activities of the different peptides both at neutral and low pH show that the presence of phenylalanine is not essential nor optimal, as the Tip, Leu, and Ile mutant are equally or more active than the wild-type component. In general, at neutral pH, the biological activities correlate well with the peptides' ability to interact with membrane lipids. Correspondingly, the permeabilization efficiencies of biological and model membranes of the various derivatives were found to be closely related to their ability to adopt alpha-helical structures, and follows the order 5L>5W>5I>5Y>wild type. The results suggest an important role for the Phe residues, in providing the peptide in a balanced manner with sufficient hydrophobicity, and therewith membrane affinity, as well as conformational flexibility. (C) 2003 Elsevier B.V. All rights reserved.