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阿尔法2预测的氨基质轻链的合规景观及其与VL域突变和聚合倾向的相关性

Sarita Puri¹, Ishaan Chaudhary¹, Arnav Khatri¹

¹Biology Department, Indian Institute of Science Education and Research, Pune, India.

Journal of molecular recognition : JMR

|September 1, 2025

概括

人工智能建模显示,来自某些生殖系的轻链 (LC) 的特定结构模式与全身轻链粉症 (AL) 聚合倾向相关,提供了新的治疗点.

科学领域:

生物化学
结构生物学
计算生物学

背景情况:

系统性轻链粉症 (AL) 是由于免疫球蛋白轻链 (LC) 错误折叠而形成的.
LCs形成具有变量 (VL) 和常量 (CL) 域的同位体,但序列变异性使治疗发展复杂化.
针对LCs独特的生殖系特异性结构特征提供了一个潜在的治疗策略.

研究的目的:

使用人工智能驱动的建模研究粉样蛋白轻链 (LC) 的生殖系特征.
将这些结构特征与AL粉样性病的临床患病率和聚合倾向相关联.
确定潜在的广泛适用的治疗粉样化病的目标.

主要方法:

利用基于AI的AlphaFold2从四个普遍的氨基基基因生殖系 (IGLV1 ((λ1),IGLV3 ((λ3),IGLV6 ((λ6),IGKV1 ((κ1)) 产生全长LC的结构模型.
与蛋白质数据库 (PDB) 存储的结构进行基准预测.
分析了二聚体构成 (开放与封闭),并将它们与聚合倾向和临床数据相关联.

主要成果:

鉴定出不同的生殖系特异性结构模式,其中λ6和λ1LC主要形成开放的二次体 (分别为86%和72%).
在48%的病例中观察到 λ3 LCs 形成开放的二元体,而 κ1 LCs 始终形成封闭的二元体.
在采用开放形状和更高的聚合倾向之间发现了强烈的相关性,反映了临床AL患病率 (λ6 > λ1 > λ3 > κ1).

结论:

细菌系特定的结构特征,特别是二分体构造,是AL粉样性聚合倾向的关键决定因素.
开放的二元构造与突变数量独立的聚合风险增加有关.
这些发现突出了生殖系特异性的结构特征,作为开发更普遍的AL粉样性病治疗的有前途的治疗点.

关键词:

艾尔粉症阿尔法折叠2 抗体轻链分子动力学模拟蛋白质错误折叠和聚合

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