Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site
Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site
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DOI：
10.1016/j.bbadis.2011.09.005
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发表时间：
2011-12-01
影响因子：
6.2
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
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作者：
Furukawa, Yoshiaki;Kaneko, Kumi;Nukina, Nobuyuki
TAR DNA结合蛋白-43(TDP-43)的聚集是肌萎缩侧索硬化症和额颞叶变性的特征。在致病条件下，TDP-43的异常切割会产生磷酸化的C末端片段(CTF)，这些片段富含在神经元包涵体中；然而，这些TDP-43片段的分子性质尚不清楚。在这里，我们显示了在TDP-43的不同位置截断的片段之间不同程度的溶解和磷酸化。截断主要在TDP-43的第二个RNA识别基序(RRM2)内进行；当截断位置在RRM2结构域中更多的C末端时，TDP-43 CTF在分化的Neuro2a细胞中基本上变得更难溶解和更多的磷酸化。我们还发现，RRM2中第三条β链的切割导致了耐十二烷基硫酸钠的可溶性低聚物的形成。因此，TDP-43片段的分子性质在很大程度上取决于其切割位置，这可能反映了不同TDP-43蛋白病变亚型之间的不同分子病理学。(C)2011爱思唯尔B.V.保留所有权利。
Aggregation of TAR DNA binding protein-43 (TDP-43) is a hallmark feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Under pathogenic conditions, abnormal cleavage of TDP-43 produces the phosphorylated C-terminal fragments (CTFs), which are enriched in neuronal inclusions; however, molecular properties of those TDP-43 fragments remain to be characterized. Here we show distinct degrees of solubility and phosphorylation among fragments truncated at different sites of TDP-43. Truncations were tested mainly within a second RNA recognition motif (RRM2) of TDP-43; when the truncation site was more C-terminal in an RRM2 domain, a TDP-43 CTF basically became less soluble and more phosphorylated in differentiated Neuro2a cells. We also found that cleavage at the third beta-strand in RRM2 leads to the formation of SDS-resistant soluble oligomers. Molecular properties of TDP-43 fragments thus significantly depend upon its cleavage site, which might reflect distinct molecular pathologies among sub-types of TDP-43 proteinopathies. (C) 2011 Elsevier B.V. All rights reserved.