Reducing the Amyloidogenicity of Functional Amyloid Protein FapC Increases Its Ability To Inhibit α-Synuclein Fibrillation
Reducing the Amyloidogenicity of Functional Amyloid Protein FapC Increases Its Ability To Inhibit α-Synuclein Fibrillation
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DOI：
10.1021/acsomega.8b03590
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发表时间：
2019-02-01
期刊：
影响因子：
4.1
通讯作者：
Otzen, Daniel Erik
中科院分区：
文献类型：
--
作者：
Christensen, Line Friis Bakmann;Jensen, Kirstine Friis;Otzen, Daniel Erik
功能性淀粉样蛋白（FA）已经进化成具有特征性交叉β结构的原纤维，其稳定生物膜并有助于细菌毒力。一些研究最多的细菌FA是卷曲蛋白CsgA，在广泛的细菌中表达，和FapC，主要由假单胞菌属的成员产生。虽然不相关，但CsgA和FapC都含有不完美的重复序列，据信这些重复序列会驱动淀粉样蛋白原纤维的形成。虽然对CsgA生物发生和纤维化了解很多，但FapC纤维化的机制仍然很少探索。在这里，我们发现，去除FapC的三个不完美的重复（FapC Delta R1 R2 R3）减缓了原纤化，但不能阻止它。FapC Delta R1 R2 R3的延迟期增加，允许二硫键形成，这进一步延迟了原纤化。值得注意的是，FapC Delta R1 R2 R3的这些二硫键键种类也显著延迟了人类α-突触核蛋白的纤维化，这是帕金森病病理学中的关键蛋白质。对于FapC Delta R1 R2 R3的还原形式，未观察到α-突触核蛋白原纤化的这种减弱。本文提出的结果阐明了FapC原纤化机制，并强调了不相关的原纤化系统如何共享这种共同的原纤形成机制，允许一种抑制蛋白的抑制剂影响完全不同的蛋白。
Functional amyloid (FA) proteins have evolved to assemble into fibrils with a characteristic cross-beta structure, which stabilizes biofilms and contributes to bacterial virulence. Some of the most studied bacterial FAs are the curli protein CsgA, expressed in a wide range of bacteria, and FapC, produced mainly by members of the Pseudomonas genus. Though unrelated, both CsgA and FapC contain imperfect repeats believed to drive the formation of amyloid fibrils. While much is known about CsgA biogenesis and fibrillation, the mechanism of FapC fibrillation remains less explored. Here, we show that removing the three imperfect repeats of FapC (FapC Delta R1R2R3) slows down the fibrillation but does not prevent it. The increased lag phase seen for FapC Delta R1R2R3 allows for disulfide bond formation, which further delays fibrillation. Remarkably, these disulfide-bonded species of FapC Delta R1R2R3 also significantly delay the fibrillation of human alpha-synuclein, a key protein in Parkinson's disease pathology. This attenuation of alpha-synuclein fibrillation was not seen for the reduced form of FapC Delta R1R2R3. The results presented here shed light on the FapC fibrillation mechanism and emphasize how unrelated fibrillation systems may share such common fibril formation mechanisms, allowing inhibitors of one fibrillating protein to affect a completely different protein.