Importin α/β and the tug of war to keep TDP-43 in solution: quo vadis?
Importin α/β and the tug of war to keep TDP-43 in solution: quo vadis?
复制标题
DOI：
10.1002/bies.202200181
复制
发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
43 kDa的反式激活反应-DNA结合蛋白(TDP-43)是一种易于聚集的核酸结合蛋白，与肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)的病因有关。这些情况的特点是不溶的TDP-43聚集在神经元细胞质中，导致细胞死亡。在疾病状态下，细胞质和核TDP-43之间的动力学发生改变，TDP-43错误定位于细胞质，破坏核孔复合体(NPC)，最终形成由C末端蛋白样结构域稳定的大纤维。在这里，我们回顾了TDP-43生物学中与其聚集相关的三个新兴和鲜为人知的方面。首先，TDP-43 N-末端结构域(NTD)附近的翻译后修饰如何促进聚集。第二，TDP-43如何在鼻咽癌中与FG-核孔素结合，破坏鼻咽癌的孔道通透性和功能。第三，进口素α/β异源二聚体如何阻止TDP-43聚集，既作为核进口转运蛋白，又作为细胞质伴侣。
The transactivation response-DNA binding protein of 43 kDa (TDP-43) is an aggregation-prone nucleic acid-binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP-43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP-43 are altered in the disease state where TDP-43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C-terminal prion-like domain. Here, we review three emerging and poorly understood aspects of TDP-43 biology linked to its aggregation. First, how post-translational modifications in the proximity of TDP-43 N-terminal domain (NTD) promote aggregation. Second, how TDP-43 engages FG-nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP-43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone.
DOI：
10.3390/molecules27134309
发表时间：
2022-07-05
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--