Elucidation of the Molecular Mechanism during the Early Events in Immunoglobulin Light Chain Amyloid Fibrillation
Elucidation of the Molecular Mechanism during the Early Events in Immunoglobulin Light Chain Amyloid Fibrillation
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免疫球蛋白轻链淀粉样纤维颤动早期事件的分子机制的阐明
DOI：
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发表时间：
2002
影响因子：
4.8
通讯作者：
A. Fink
中科院分区：
文献类型：
--
作者：
P. Souillac;V. Uversky;I. Millett;R. Khurana;S. Doniach;A. Fink
轻链淀粉样变性涉及免疫球蛋白的单克隆性轻链可变区作为不溶性纤维的全身性病理沉积。可变区LEN是从一名没有明显淀粉样变性的患者身上获得的；然而，LEN在体外形成纤维，在轻微不稳定的条件下。用多种探头研究了原纤化的体外动力学。纤维形成的速度高度依赖于初始蛋白质浓度。与大多数淀粉样蛋白系统相比，随着LEN浓度的增加，动力学变得缓慢。当蛋白质浓度较高时，在构象变化和纤维形成之间存在明显的滞后，这与可溶性非途径寡聚物种的形成和分支途径的形成相一致。通过小角x射线散射证实了异径物种的存在。在低蛋白质浓度时，结构重排与纤维形成同时发生，这表明没有形成旁路物种。这些数据与纤颤模型一致，在该模型中，二聚体LEN(在高蛋白浓度下)通过与纤颤途径上的中间体相互作用抑制纤维形成，并导致非途径中间体的形成。
Light chain amyloidosis involves the systemic pathologic deposition of monoclonal light chain variable domains of immunoglobulins as insoluble fibrils. The variable domain LEN was obtained from a patient who had no overt amyloidosis; however, LEN forms fibrils in vitro, under mildly destabilizing conditions. The in vitro kinetics of fibrillation were investigated using a wide variety of probes. The rate of fibril formation was highly dependent on the initial protein concentration. In contrast to most amyloid systems, the kinetics became slower with increasing LEN concentrations. At high protein concentrations a significant lag in time was observed between the conformational changes and the formation of fibrils, consistent with the formation of soluble off-pathway oligomeric species and a branched pathway. The presence of off-pathway species was confirmed by small angle x-ray scattering. At low protein concentrations the structural rearrangements were concurrent with fibril formation, indicating the absence of formation of the off-pathway species. The data are consistent with a model for fibrillation in which a dimeric form of LEN (at high protein concentration) inhibits fibril formation by interaction with an intermediate on the fibrillation pathway and leads to formation of the off-pathway intermediate.
影响因子：
2.9
作者：
Lai, ZH;Colon, W;Kelly, JW
通讯作者：
Kelly, JW
影响因子：
2.9
作者：
Sreerama, N;Manning, MC;Woody, RW
通讯作者：
Woody, RW
影响因子：
4
作者：
Solomon,A
通讯作者：
Solomon,A