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首页> 外文期刊>Biochemistry >Heterogeneity in Primary Structure,Post-Translational Modifications,and Germline Gene Usage of Nine Full-Length Amyloidogenic kappa1 Immunoglobulin Light Chains
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Heterogeneity in Primary Structure,Post-Translational Modifications,and Germline Gene Usage of Nine Full-Length Amyloidogenic kappa1 Immunoglobulin Light Chains

机译：九个全长淀粉样蛋白κ免疫球蛋白轻链的一级结构，翻译后修饰和种系基因使用的异质性。

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摘要

Immunoglobulin light chain amyloidosis is a protein misfolding disease in which a monoclonal immunoglobulin (Ig) light chain (LC) with a critically folded beta-conformation self-aggregates to form highly ordered,nonbranching amyloid fibrils.The insoluble nature of amyloid fibrils ultimately results in the extracellular deposition of the LC in tissues and organs throughout the body.Structural features that confer amyloidogenic properties on an Ig LC likely include amino acid sequence variations and post-translational modifications,but the specific natures of these changes remain to be defined.As part of an exploration of the effective range of amyloidogenic modifications,this study details the structural and genetic analyses of nine kappa 1 LC proteins.Urinary LCs were purified by size exclusion chromatography using FPLC,and structural analyses were performed by electrospray ionization,matrix-assisted laser desorption/ionization,and tandem mass spectrometry.RT-PCR amplification,cloning,and sequencing of the monoclonal LC genes were accomplished using bone marrow-derived mRNA.Clinical data were reviewed retrospectively.Characterization of the urinary kappa 1 LCs revealed extensive post-translational modification in all proteins,in addition to somatic mutations expected on the basis of results from genetic analyses.Post-translational modifications included disulfide-linked dimerization,S-cysteinylation,gly-cosylation,fragmentation,S-sulfonation,and 3-chlorotyrosine formation.Genetic analyses showed that several LC variable region germline gene donors were represented including 018/08,012/02,L15,and L5.Clinical features included soft tissue,cardiac,renal,and hepatic involvement.This study demonstrated the extensive heterogeneity in primary structure,post-translational modifications,and germline gene usage that occurred in nine amyloidogenic kappa 1 LC proteins.
机译：免疫球蛋白轻链淀粉样变性是一种蛋白质错误折叠疾病，其中具有关键折叠的β构象的单克隆免疫球蛋白（Ig）轻链（LC）自聚集形成高度有序的，无分支的淀粉样原纤维。淀粉样原纤维的不溶性最终导致在Ig LC上赋予淀粉样蛋白生成特性的结构特征可能包括氨基酸序列变异和翻译后修饰，但这些改变的具体性质仍有待确定。在探索淀粉样变性修饰有效范围的基础上，本研究详细介绍了九种κ1 LC蛋白的结构和遗传分析。尿液中的LC通过FPLC尺寸排阻色谱法纯化，并通过电喷雾电离，基质辅助激光进行结构分析解吸/电离和串联质谱.RT-PCR扩增，克隆，单克隆LC基因的测序和测序均使用骨髓来源的mRNA进行。回顾性分析了临床数据。尿kappa 1 LC的特性表明，除蛋白质外，根据结果预期发生体细胞突变，所有蛋白均具有广泛的翻译后修饰。翻译后修饰包括二硫键连接的二聚化，S-半胱氨酰化，糖基-糖基化，片段化，S-磺化和3-氯酪氨酸的形成。遗传分析表明，代表了几个LC可变区种系基因供体，包括018 / 08,012 / 02，L15和L5。临床特征包括软组织，心脏，肾脏和肝脏受累。这项研究表明，在9个淀粉样生成的κ1 LC中，一级结构，翻译后修饰和种系基因的使用广泛异质。蛋白质。

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