Inhibition of amyloid fiber assembly by both BiP and its target peptide
Inhibition of amyloid fiber assembly by both BiP and its target peptide
复制标题
DOI：
10.1016/s1074-7613(00)00043-1
复制
发表时间：
2000-10-01
期刊：
影响因子：
32.4
通讯作者：
Argon, Y
中科院分区：
文献类型：
--
作者：
Davis, DP;Raffen, R;Argon, Y
免疫球蛋白轻链(LC)通常是一种可溶性的分泌性蛋白，但一些LC会聚集成有序的纤维，这些纤维沉积在组织中会导致淀粉样变性和器官衰竭。在这里，我们重建了体外纤维的形成，并表明预制的纤维可以使可溶性LC聚合成核。由于体细胞突变产生了多个相关的LC序列，所以这种类似Pron的行为具有重要的生理学意义。此外，我们证明了BiP和一个与sip的主要LC结合位点相同的合成肽可以抑制体外形成的纤维和整个LC在细胞内的聚集。我们认为LC通过蛋白质间环交换形成纤维，潜在的构象变化应该服从药物治疗。
Immunoglobulin light chain (LC) normally is a soluble, secreted protein, but some LC assemble into ordered fibrils whose deposition in tissues results in amyloidosis and organ failure. Here we reconstitute fibril formation in vitro and show that preformed fibrils can nucleate polymerization of soluble LC. This prion-like behavior has important physiological implications, since somatic mutations generate multiple related LC sequences. Furthermore, we demonstrate that fibril formation in vitro and aggregation of whole LC within cells are inhibited by BiP and by a synthetic peptide that is identical to a major LC binding site for Sip. We propose that LC form fibrils via an interprotein loop swap and that the underlying conformational change should be amenable to drug therapy.