Domain a' of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation
Domain a' of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation
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DOI：
10.1007/s12192-009-0157-2
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Wang, Chih-chen
中科院分区：
文献类型：
--
作者：
Cheng, Han;Wang, Lei;Wang, Chih-chen
突触核蛋白（α Syn）是形成于中脑多巴胺能神经元的路易小体的主要成分，是帕金森病的病理特征。最近有研究表明，它可诱导内质网应激并损害内质网功能。然而，内质网对α - Syn毒性反应的机制尚不清楚。在本研究中，我们发现蛋白二硫异构酶（PDI）是内质网中丰富的应激蛋白，在体外有效地抑制α - Syn纤维的形成。在abb'xa‘c结构的PDI分子中，结构域a’被发现是PDI抑制α Syn纤维形成的必要和充分条件。进一步发现PDI更热衷于与α Syn纤维形成过程中形成的中间物种结合，并且在滞后期结合更加强烈。我们的研究结果为PDI在保护内质网免受许多神经退行性疾病中错误折叠蛋白积累的有害影响中的作用提供了新的见解。
alpha-Synuclein (alpha Syn) is the main component of Lewy bodies formed in midbrain dopaminergic neurons which is a pathological characteristic of Parkinson's disease. It has been recently showed to induce endoplasmic reticulum (ER) stress and impair ER functions. However, the mechanism of how ER responds to alpha Syn toxicity is poorly understood. In the present study, we found that protein disulfide isomerase (PDI), a stress protein abundant in ER, effectively inhibits alpha Syn fibril formation in vitro. In PDI molecule with a structure of abb'xa'c, domain a' was found to be essential and sufficient for PDI to inhibit alpha Syn fibril formation. PDI was further found to be more avid for binding with intermediate species formed during alpha Syn fibril formation, and the binding was more intensive in the later lag phase. Our results provide new insight into the role of PDI in protecting ER from the deleterious effects of misfolded protein accumulation in many neurodegenerative diseases.