Structural and functional implications of a proline residue in the antimicrobial peptide gaegurin
Structural and functional implications of a proline residue in the antimicrobial peptide gaegurin
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DOI：
10.1046/j.1432-1327.1999.00917.x
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发表时间：
1999-12-01
期刊：
影响因子：
--
通讯作者：
Choi, BS
中科院分区：
文献类型：
--
作者：
Suh, JY;Lee, YT;Choi, BS
虽然它通常被称为螺旋破坏剂，但在许多肽和蛋白质的α-螺旋区域中发现了脯氨酸残基。抗菌肽gaegurin具有α-螺旋结构，中心有一个脯氨酸残基（P14）。通过多种光谱学方法、约束分子动力学和生物活性测定，对gaegurin及其丙氨酸衍生物（P14 A）的结构和活性进行了研究。P14和P14 A在溶液中均表现出协同螺旋形成，但与P14 A相比，P14的螺旋稳定性显著降低。化学位移分析表明，这两种肽形成弯曲的螺旋和P14显示在中央脯氨酸周围区域的稳定性降低。然而，氢交换数据显示稳定的酰胺质子的位置显着差异。P14在弯曲螺旋的凹侧显示出稳定区域，而P14 A在螺旋的中央转弯处显示出稳定区域。与P14 A的均匀螺旋相反，P14的模型结构表现出明显的扭结。两种肽对带负电荷的脂质显示出相当的结合亲和力，而P14对中性脂质的亲和力大大降低。由于α-螺旋的不稳定性，P14表现出比P14 A更强的抗菌活性。因此，螺旋肽与脂质膜之间的静电相互作用被认为是抗菌活性的主导因素。此外，螺旋稳定性可以调节由静电相互作用驱动的肽与膜的结合。P14是比P14 A更有效的抗菌剂的观察意味着P14的螺旋扭结在细菌膜的破坏中起重要作用。
Although it is commonly known as a helix breaker, proline residues have been found in the alpha-helical regions of many peptides and proteins. The antimicrobial peptide gaegurin displays alpha-helical structure and has a central proline residue (P14). The structure and activity of gaegurin and its alanine derivative (P14A) were determined by various spectroscopic methods, restrained molecular dynamics, and biological assays. Both P14 and P14A exhibited cooperative helix formation in solution, but the helical stability of P14 was reduced substantially when compared to that of P14A. Chemical-shift analysis indicated that both of the peptides formed curved helices and that P14 showed diminished stability in the region around the central proline. However, hydrogen-exchange data revealed remarkable differences in the location of stable amide protons. P14 showed a stable region in the concave side of the curved helix, while P14A exhibited a stable region in the central turn of the helix. The model structure of P14 exhibited a pronounced kink, in contrast to,the uniform helix of P14A. Both peptides showed comparable binding affinities for negatively charged lipids, while P14 had a considerably reduced affinity for a neutral lipid. With its destabilized alpha-helix, P14 exhibited greater antibacterial activity than did P14A, Hence, electrostatic interaction between helical peptides and lipid membranes is believed to be the dominant factor for antibacterial activity. Moreover, helical stability can modulate peptide binding to membranes that is driven by electrostatic interactions. The observation that P14 is a more potent antibacterial agent than P14A implies that the helical kink of P14 plays an important role in the disruption of bacterial membranes.