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Pinpointing the interaction site between semaphorin-3A and its inhibitory peptide
Journal of Peptide Science ( IF 2.1 ) Pub Date : 2022-10-26 , DOI: 10.1002/psc.3460
Kevin Kretschmer 1 , Jan Stichel 1 , Kathrin Bellmann-Sickert 1 , Lars Baumann 2 , Donald Bierer 2 , Bernd Riedl 2 , Annette G Beck-Sickinger 1
Affiliation  

Semaphorin-3A (Sema-3A) is a chemorepellant protein with various biological functions, including kidney development. It interacts with a protein complex consisting of the receptors neuropilin-1 (NRP-1) and plexin-A1. After acute kidney injury, Sema-3A is overexpressed and secreted, leading to a loss of kidney function. The development of peptide inhibitors is a promising approach to modulate the interaction of Sema-3A with its receptor NRP-1. Few interaction points between these binding partners are known. However, an immunoglobulin-like domain-derived peptide of Sema-3A has shown a positive effect on cell proliferation. To specify these interactions between the peptide inhibitor and the Sema-3A–NRP-1 system, the peptides were modified with the photoactivatable amino acids 4-benzoyl-l-phenylalanine or photo-l-leucine by solid-phase peptide synthesis. Activity was tested by an enzyme-linked immunosorbent-based binding assay, and crosslinking experiments were analyzed by Western blot and mass spectrometry, demonstrating a specific binding site of the peptide at Sema-3A. The observed signals for Sema-3A-peptide interaction were found in a defined area of the Sema domain, which was also demonstrated to be involved in NRP-1 binding. The presented data identified the interaction site for further development of therapeutic peptides to treat acute kidney injury by blocking the Sema-3A–NRP-1 interaction.

中文翻译:

精确定位 semaphorin-3A 与其抑制肽之间的相互作用位点

Semaphorin-3A (Sema-3A) 是一种化学排斥蛋白,具有多种生物学功能,包括肾脏发育。它与由受体 neuropilin-1 (NRP-1) 和 plexin-A1 组成的蛋白质复合物相互作用。急性肾损伤后,Sema-3A 过度表达和分泌,导致肾功能丧失。肽抑制剂的开发是调节 Sema-3A 与其受体 NRP-1 相互作用的有前途的方法。这些绑定合作伙伴之间的交互点很少为人所知。然而,Sema-3A 的免疫球蛋白样结构域衍生肽已显示出对细胞增殖的积极作用。为了详细说明肽抑制剂与 Sema-3A–NRP-1 系统之间的这些相互作用,用光活化氨基酸 4-苯甲酰基-l-苯丙氨酸或光-l-亮氨酸通过固相肽合成。通过基于酶联免疫吸附剂的结合测定测试活性,并通过蛋白质印迹和质谱分析交联实验,证明肽在 Sema-3A 的特异性结合位点。观察到的 Sema-3A-肽相互作用信号出现在 Sema 结构域的一个确定区域,该区域也被证明与 NRP-1 结合有关。提供的数据确定了进一步开发治疗性肽的相互作用位点,通过阻断 Sema-3A–NRP-1 相互作用来治疗急性肾损伤。
更新日期:2022-10-26
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