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首页> 外文期刊>Biochemistry >Structural Transformations of Oligomeric Intermediates in the Fibrillation of the Immunoglobulin Light Chain LEN.
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Structural Transformations of Oligomeric Intermediates in the Fibrillation of the Immunoglobulin Light Chain LEN.

机译：免疫球蛋白轻链LEN的原纤化中的寡聚中间体的结构转化。

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摘要

LEN is a kappaIV immunoglobulin light chain variable domain from a patient suffering from multiple myeloma but with no evidence of amyloid fibrils. However, fibrils are formed when LEN solutions are agitated under mildly destabilizing conditions. Surprisingly, an inverse concentration dependence was observed on the kinetics of fibril formation because of the formation of off-pathway soluble oligomers at high protein concentration. Despite the fact that most of the protein is present in the off-pathway intermediates at relatively early times of aggregation, eventually all the protein forms fibrils. Thus, a structural rearrangement from the non fibril-prone off-pathway oligomers to a more fibril-prone species must occur. A variety of techniques were used to monitor changes in the size, secondary structure, solvent accessibility, and intrinsic stability of the oligomers, as a function of incubation time. The structural rearrangement was accompanied by a significant increase of disordered secondary structure, an increase in solvent accessibility, and a decrease in intrinsic stability of the soluble oligomeric species. We conclude that fibrils arise from the oligomers containing a less stable conformation of LEN, either directly or via dissociation. This is the first fibrillating system in which soluble off-pathway oligomeric intermediates have been shown to be the major transient species and in which fibrillation occurs from a relatively unfolded conformation present in these intermediates.
机译：LEN是患有多发性骨髓瘤但没有淀粉样原纤维证据的患者的kappaIV免疫球蛋白轻链可变域。但是，在适度去稳定的条件下搅拌LEN溶液时会形成原纤维。出人意料的是，由于在高蛋白浓度下会形成路旁可溶性低聚物，因此观察到浓度反演对原纤维形成的动力学。尽管大多数蛋白质在相对早期聚集时都存在于非通路中间体中，但最终所有蛋白质都形成了原纤维。因此，必须发生从非原纤维倾向的路径外低聚物到更原纤维倾向的物种的结构重排。多种技术被用来监测寡聚物的大小，二级结构，溶剂可及性和固有稳定性的变化，这些变化是孵育时间的函数。结构重排伴随着无序二级结构的显着增加，溶剂可及性的增加以及可溶性低聚物种类的固有稳定性的降低。我们得出的结论是，原纤维是由直接或通过解离而含有不太稳定的LEN构象的寡聚物产生的。这是第一个原纤化系统，其中已显示出可溶性的路径外低聚中间体是主要的瞬态物种，并且原纤化是由这些中间体中存在的相对未折叠的构象发生的。

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