Role of complementarity-determining regions 1 and 3 in pathologic amyloid formation by human immunoglobulin κ1 light chains.

IF 5.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Elena S Klimtchuk, Daniele Peterle, Esther Bullitt, Lawreen H Connors, John R Engen, Olga Gursky
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引用次数: 0

Abstract

Background: Immunoglobulin light chain (LC) amyloidosis is a life-threatening disease complicated by vast numbers of patient-specific mutations. We explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01.

Methods: Hydrogen-deuterium exchange mass spectrometry analysis of conformational dynamics in recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation and amyloidogenic sequence propensity. The results were mapped on the structures of native and fibrillary proteins.

Results: Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower, suggesting different major factors influencing amyloidogenesis. In 33*01-related amyloid LC, these factors involved destabilization of the native structure and probable stabilization of amyloid. The atypical behavior of 39*01-related amyloid LC stemmed from increased dynamics/exposure of amyloidogenic segments in βC'V and βEV that could initiate aggregation and decreased dynamics/exposure near the Cys23-Cys88 disulfide.

Conclusions: The results suggest distinct amyloidogenic pathways for closely related LCs and point to the complementarity-defining regions CDR1 and CDR3, linked via the conserved internal disulfide, as key factors in amyloid formation.

互补决定区1和3在人免疫球蛋白κ1轻链病理淀粉样蛋白形成中的作用。
背景:免疫球蛋白轻链(LC)淀粉样变性是一种危及生命的疾病,并发大量患者特异性突变。我们研究了14个与κ1家族种系基因IGKVLD-33*01和IGKVLD-39*01相关的患者源性和工程化蛋白。方法:将重组lc及其片段的构象动力学的氢-氘交换质谱分析与热稳定性、蛋白水解敏感性、淀粉样蛋白形成和淀粉样蛋白序列倾向的研究相结合。结果被映射到天然蛋白和原纤维蛋白的结构上。结果:两个κ1亚家族的蛋白存在意想不到的差异。与种系淀粉样蛋白相比,IGKVLD-33*01相关的淀粉样蛋白LC稳定性较差,淀粉样蛋白形成速度较快,而IGKVLD-39*01相关的淀粉样蛋白LC稳定性相似,淀粉样蛋白形成速度较慢,说明影响淀粉样蛋白形成的主要因素不同。在33*01相关的淀粉样蛋白LC中,这些因素涉及到天然结构的不稳定和淀粉样蛋白可能的稳定。39*01相关淀粉样蛋白LC的非典型行为源于βC'V和βEV中淀粉样蛋白片段的动态/暴露增加,这可能引发聚集,并降低了Cys23-Cys88二硫化物附近的动态/暴露。结论:研究结果表明,密切相关的LCs具有不同的淀粉样蛋白形成途径,并指出通过保守的内部二硫化物连接的互补性定义区域CDR1和CDR3是淀粉样蛋白形成的关键因素。
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来源期刊
Amyloid-Journal of Protein Folding Disorders
Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学
CiteScore
10.60
自引率
10.90%
发文量
48
审稿时长
6-12 weeks
期刊介绍: Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.
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