Conformational dynamics and misfolding of the fibril precursor proteins studied by NMR

核磁共振研究原纤维前体蛋白的构象动力学和错误折叠

• 批准号: 422489899
• 负责人: Professor Dr. Bernd Reif
• 金额: --
• 依托单位: Professur für Festkörper-NMR-Spektroskopie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422489899?language=en
• 关键词: Conformational; dynamics; misfolding; fibril; precursor

Systemic AL amyloidosis arises from the misfolding and/or truncation of immunoglobulin light chains and the deposition of amyloid fibrils consisting of light chain fragments, termed AL proteins. In this project we will analyze the structure and the misfolding of the light chains at a residue-specific, if not atom-specific, levels. The detailed aims will be: (i) To characterize with nuclear magnetic resonance the structure and misfolding of full-length light chains. (ii) To characterize with nuclear magnetic resonance the misfolding kinetics of the AL proteins. (iii) To analyse the structure of AL protein aggregates by solid-state nuclear magnetic resonance. Through this work we will test the hypothesis that an extensive restructuring of the protein conformation is necessary to account for the heterogeneity and the localization of the aggregates in patient tissue. We will compare the structural properties of proteins derived from AL patients with proteins derived from multiple myeloma without AL amyloidosis. Through analysis of the interactions between the variable light and the constant light domain we will define as to whether or not these interactions interfere with the further processing of the light chains. Comparison of structures obtained from differing sequences shall enable the derivation of more general principles for AL amyloid fibril formation.

全身性AL淀粉样变性是由免疫球蛋白光链的错误折叠和/或截断引起的，以及由轻链片段组成的淀粉样蛋白原纤维的沉积，称为Al蛋白。在这个项目中，我们将分析在残基特异性（如果不是原子特异性的）水平上，光链的结构和错误折叠。详细的目的将是：（i）用核磁共振表征全长光链的结构和错误折叠。 （ii）用核磁共振表征Al蛋白的错误折叠动力学。 （iii）通过固态核磁共振分析Al蛋白聚集体的结构。通过这项工作，我们将检验以下假设：蛋白质构象的广泛重组对于说明患者组织中骨料的异质性和定位是必要的。我们将比较来自源自多发性骨髓瘤的蛋白质患者的蛋白质的结构特性。通过分析可变光和恒定光结构域之间的相互作用，我们将定义这些相互作用是否干扰光链的进一步处理。从不同序列获得的结构的比较应能够衍生出淀粉样蛋白原纤维形成的更一般原理。