The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria.
The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria.
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DOI：
10.1186/s12934-015-0284-7
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发表时间：
2015-07-11
影响因子：
6.4
通讯作者：
Ventura S
中科院分区：
文献类型：
--
作者：
Navarro S;Marinelli P;Diaz-Caballero M;Ventura S
蛋白质内含物的形成与许多人类疾病的发生有关。发现含有氨基酸组成类似于酵母朊病毒结构域的氨基酸组成的固有无序区域的人RNA结合蛋白，如TDP-43或FUS，在不同的神经退行性疾病中聚集。由这些蛋白质形成的细胞内包涵体的结构仍然不清楚，这些沉积物是否具有淀粉样蛋白的性质是一个有争议的问题。最近，TDP-43的聚集已经在细菌中建模，显示TDP-43包涵体（IB）是无定形的，但本质上具有神经毒性。这一观察结果提出了一个问题，即这些人类朊病毒样蛋白聚集体中缺乏有序结构是否确实是它们在不同病理状态下毒性的根本原因。在这里，我们的特点是由人类朊病毒样RNA加工蛋白HNRPDL形成的IBs。HNRPDL与肢带型肌营养不良症1G的发展相关，并与TDP-43共享结构域结构。我们发现，HNRPDL IB显示出特征性的淀粉样蛋白标志，因为这些聚集体在体外和细胞内与淀粉样蛋白染料结合，它们富含分子间β-折叠构象并含有内部淀粉样蛋白样纤维结构。此外，尽管它们的有序结构，HNRPDL IB是高度神经毒性的。我们的研究结果表明，至少有一些由人类朊病毒样蛋白聚集引起的疾病将依赖于经典淀粉样蛋白组装体的形成，而不是由无定形聚集体引起的。它们还说明了微生物细胞工厂模拟淀粉样蛋白聚集的能力。本文的在线版本（doi：10.1186/s12934-015-0284-7）包含补充材料，可供授权用户使用。
The formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states. Here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic. Our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation. The online version of this article (doi:10.1186/s12934-015-0284-7) contains supplementary material, which is available to authorized users.
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DOI：
10.1111/j.1432-1033.1990.tb19354.x
发表时间：
1990-10-24
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
GOORMAGHTIGH, E;CABIAUX, V;RUYSSCHAERT, JM
通讯作者：
RUYSSCHAERT, JM
影响因子：
4.3
作者：
Castillo V;Ventura S
通讯作者：
Ventura S
影响因子：
5.3
作者：
Falsone A;Falsone SF
通讯作者：
Falsone SF
影响因子：
6.4
作者：
Espargaró A;Villar-Piqué A;Sabaté R;Ventura S
通讯作者：
Ventura S
影响因子：
5.7
作者：
Da Cruz S;Cleveland DW
通讯作者：
Cleveland DW