Four structural risk factors identify most fibril-forming kappa light chains
Four structural risk factors identify most fibril-forming kappa light chains
复制标题
DOI：
10.3109/13506120009146835
复制
发表时间：
2000-09-01
期刊：
影响因子：
--
通讯作者：
Stevens, FJ
中科院分区：
文献类型：
--
作者：
Stevens, FJ
抗体轻链（LCs）包含了淀粉样变性中结构最多样化的蛋白家族。许多抗体lc具有损害其稳定性和溶解度的结构特征，导致其组装成原纤维，并在多发性骨髓瘤和原发性淀粉样变性期间过量产生时导致其随后的病理沉积。抗体lc中特定的氨基酸变异解释了纤维的形成和淀粉样蛋白的形成还没有被确定。本研究的重点是在人类LCs的kappa 1家族淀粉样蛋白的发生。对目前100多例产生kappa 1 LCs的患者（其中37例为淀粉样变性）蛋白质初级结构数据库的重新分析，揭示了可能导致淀粉样变性的明显结构特征。这些特征包括在涉及轻链可变结构域（V-L）中约20%的氨基酸位置的位点上发生突变，从而丢失保守残基或获得特定残基。此外，80%的kappa 1淀粉样变性V(L)s可以通过三个单位点取代中的至少一个或通过突变获得n链糖基化位点来识别。这些发现表明，通过分析原纤维结构来预测原纤维倾向是可行的。
Antibody light chains (LCs) comprise the most structurally diverse family of proteins involved in amyloidosis. Many antibody LCs incorporate structural features that impair their stability and solubility, leading to their assembly into fibrils and to their subsequent pathological deposition when produced in excess during multiple myeloma and primary amyloidosis. The particular amino acid variations in antibody LCs that account for fibril formation and amyloidogenesis have not been identified. This study focuses on amyloidogenesis within the kappa 1 family of human LCs. Reanalysis of the current database of primary structures of proteins from more than 100 patients who produced kappa 1 LCs, 37 of which were amyloidogenic, reveals apparent structural features that may contribute to amyloidosis. These features include loss of conserved residues or the gain of particular residues through mutation at sites involving a repertoire of approximately 20% of the amino acid positions in the light chain variable domain (V-L). Moreover, 80% of all kappa 1 amyloidogenic V(L)s are identifiable by the presence of at least one of three single-site substitutions or the acquisition of an N-linked glycosylation site through mutations. These findings suggest that it is feasible to predict fibril propensity by analysis of primary structure.