结构位置决定了 KR-12 碱性氨基酸的功能作用，KR-12 是来自人类导管素 LL-37 的最小抗菌肽。,RSC Advances

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结构位置决定了 KR-12 碱性氨基酸的功能作用，KR-12 是来自人类导管素 LL-37 的最小抗菌肽。
RSC Advances ( IF 3.9 ) Pub Date : 2013-08-09 00:00:00 , DOI: 10.1039/c3ra42599a
Biswajit Mishra ₁ , Raquel F Epand ₂ , Richard M Epand ₂ , Guangshun Wang ₁

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阳离子抗菌肽是公认的开发新一代抗菌剂以对抗超级细菌的模板。人类导管素 LL-37 是人类先天免疫中必不可少的宿主防御分子。以前，我们将 KR-12 鉴定为 LL-37 中最小的抗菌肽。KR-12 的活性谱较窄，因为它对革兰氏阴性大肠杆菌有活性，但对革兰氏阳性金黄色葡萄球菌无活性. 然而，KR-12 碱性氨基酸的功能作用尚未阐明。KR-12 阳离子氨基酸的丙氨酸扫描为它们在肽活性中的独特作用提供了证据。细菌杀伤和膜渗透实验表明，R23A 和 K25A 突变体以及赖氨酸到精氨酸的突变体比 KR-12 更有效。KR-12 的另外三个阳离子残基（K18、R19 和 R29）位于两亲螺旋的亲水面，在聚集阴离子脂质或溶血方面似乎比界面区域中的 R23 和 K25 更重要。虽然界面 R23 或 K25 的缺失降低了肽的螺旋度，强调了其在膜结合中的重要作用，在这种情况下，KR-12 肽活性的总体增加可归因于增加的肽疏水性超过了基本电荷的作用。相比之下，界面 R23 或 K25 的突变降低了 GF-17 的肽杀菌活性，GF-17 是一种重叠的、疏水性更强的肽，也源自 LL-37。因此，肽的疏水环境决定了界面碱性残基的丙氨酸取代是增加还是降低膜渗透和肽活性。

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Structural location determines functional roles of the basic amino acids of KR-12, the smallest antimicrobial peptide from human cathelicidin LL-37.

Cationic antimicrobial peptides are recognized templates for developing a new generation of antimicrobials to combat superbugs. Human cathelicidin LL-37 is an essential host defense molecule in human innate immunity. Previously, we identified KR-12 as the smallest antibacterial peptide of LL-37. KR-12 has a narrow activity spectrum since it is active against Gram-negative Escherichia coli but not Gram-positive Staphylococcus aureus. The functional roles of the basic amino acids of KR-12, however, have not yet been elucidated. An alanine scan of cationic amino acids of KR-12 provided evidence for their distinct roles in the activities of the peptides. Bacterial killing and membrane permeation experiments indicate that the R23A and K25A mutants, as well as the lysine-to-arginine mutant, were more potent than KR-12. Another three cationic residues (K18, R19, and R29) of KR-12, which are located in the hydrophilic face of the amphiphathic helix, appeared to be more important in clustering anionic lipids or hemolysis than R23 and K25 in the interfacial region. While the loss of interfacial R23 or K25 reduced peptide helicity, underscoring its important role in membrane binding, the overall increase in peptide activity of KR-12 could be ascribed to the increased peptide hydrophobicity that outweighed the role of basic charge in this case. In contrast, the mutations of interfacial R23 or K25 reduced peptide bactericidal activity of GF-17, an overlapping, more hydrophobic and potent peptide also derived from LL-37. Thus, the hydrophobic context of the peptide determines whether an alanine substitution of an interfacial basic residue increases or decreases membrane permeation and peptide activity.

更新日期：2013-08-09

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