Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion
Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion
复制标题
TDP-43 蛋白淀粉样蛋白核心区的结构转变启动其聚集和细胞质包涵体
DOI：
10.1074/jbc.m113.463828
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发表时间：
2013-07-05
影响因子：
4.8
通讯作者：
Hu, Hong-Yu
中科院分区：
文献类型：
--
作者：
Jiang, Lei-Lei;Che, Mei-Xia;Hu, Hong-Yu
TDP-43 （43 kDa的TAR dna结合蛋白）是肌萎缩性侧索硬化症和泛素额颞叶痴呆的主要沉积蛋白。在柔性c端区域发现的大量基因突变与疾病病理有关。我们研究了TDP-43聚集的分子决定因素及其潜在机制。我们发现疏水斑块（残基318-343）是淀粉样蛋白聚集的核心。生物物理研究表明，同源肽在溶液中形成螺旋-转-螺旋结构，而在聚集过程中从α -螺旋结构转变为β -片结构。该核心区域的突变或缺失显著降低了全长TDP-43（或TDP-35片段）在细胞中的聚集和胞质内含物。因此，淀粉样核的结构转变引发了TDP-43的聚集和细胞质包涵体的形成。这个特殊的核心区域为设计小分子化合物减轻TDP-43蛋白病变提供了一个潜在的治疗靶点。
TDP-43 (TAR DNA-binding protein of 43 kDa) is a major deposited protein in amyotrophic lateral sclerosis and frontotemporal dementia with ubiquitin. A great number of genetic mutations identified in the flexible C-terminal region are associated with disease pathologies. We investigated the molecular determinants of TDP-43 aggregation and its underlying mechanisms. We identified a hydrophobic patch (residues 318-343) as the amyloidogenic core essential for TDP-43 aggregation. Biophysical studies demonstrated that the homologous peptide formed a helix-turn-helix structure in solution, whereas it underwent structural transformation from an alpha-helix to a beta-sheet during aggregation. Mutation or deletion of this core region significantly reduced the aggregation and cytoplasmic inclusions of full-length TDP-43 (or TDP-35 fragment) in cells. Thus, structural transformation of the amyloidogenic core initiates the aggregation and cytoplasmic inclusion formation of TDP-43. This particular core region provides a potential therapeutic target to design small-molecule compounds for mitigating TDP-43 proteinopathies.