Deciphering the Molecular Dance: Exploring the Dynamic Interplay Between Mouse Insulin B9–23 Peptides and their Variants

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Aleksandra Antevska, Kayla A. Hess, Connor C. Long, Ethan J. Walker, Joshua H. Jang, Riellie J. DeSoto, Kristi L. Lazar Cantrell, Lauren E. Buchanan* and Thanh D. Do*, 
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Abstract

Type 1 diabetes results from the autoimmune destruction of pancreatic insulin-producing β-cells, primarily targeted by autoreactive T cells that recognize insulin B9–23 peptides as antigens. Using drift tube ion mobility spectrometry-mass spectrometry, transmission electron microscopy, and two-dimensional infrared spectroscopy, we characterized mouse insulin 1 B9–23 (Ins1 B9–23), insulin 2 B9–23 (Ins2 B9–23), along with two of their mutants, Ins2 B9–23 Y16A and Ins2 B9–23 C19S. Our findings indicate that Ins1 B9–23 and the Ins2 Y16A mutant exhibit rapid fibril formation, whereas Ins2 B9–23 and the Ins2 C19S mutant show slower fibrillization and a structural rearrangement from globular protofibrils to fibrillar aggregates. These differences in aggregation behaviors also manifest in interactions with (−)epigallocatechin gallate (EGCG), a canonical amyloid inhibitor. EGCG effectively disrupts the fibrils formed by Ins1 B9–23 and the Y16A mutant. However, it proves ineffective in preventing fibril formation of Ins2 B9–23 and the C19S mutant. These results establish a strong correlation between the aggregation behaviors of these peptides and their divergent effects on anti-islet autoimmunity.

Abstract Image

解密分子舞蹈:探索小鼠胰岛素 B9-23 肽及其变体之间的动态相互作用
1 型糖尿病是胰腺分泌胰岛素的 β 细胞遭到自身免疫性破坏的结果,这种破坏主要是由识别胰岛素 B9-23 肽为抗原的自身反应性 T 细胞引起的。我们利用漂移管离子迁移谱-质谱分析法、透射电子显微镜和二维红外光谱法鉴定了小鼠胰岛素 1 B9-23(Ins1 B9-23)、胰岛素 2 B9-23(Ins2 B9-23)及其两个突变体 Ins2 B9-23 Y16A 和 Ins2 B9-23 C19S。我们的研究结果表明,Ins1 B9-23 和 Ins2 Y16A 突变体显示出快速的纤维形成,而 Ins2 B9-23 和 Ins2 C19S 突变体则显示出较慢的纤维化以及从球状原纤维到纤维状聚集体的结构重排。这些聚集行为上的差异还体现在与(-)表没食子儿茶素没食子酸酯(EGCG)的相互作用上,EGCG是一种典型的淀粉样蛋白抑制剂。EGCG 能有效破坏 Ins1 B9-23 和 Y16A 突变体形成的纤维。然而,事实证明它不能有效阻止Ins2 B9-23和C19S突变体形成纤维。这些结果确定了这些肽的聚集行为与它们对抗胰岛自身免疫的不同作用之间的密切联系。
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来源期刊
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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