Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
Nat Commun. 2012 Apr 3;3:766. doi: 10.1038/ncomms1766.
The degraded, misfolded C terminus of TAR DNA-binding protein-43 is associated with a wide spectrum of neurodegenerative diseases, particularly frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. However, the precise mechanism of pathological cleavage of the TAR DNA-binding protein-43 remains unknown. Here we show that the TAR DNA-binding protein-43 C-terminal protein physically interacts with itself or with the cellular-folded yeast prion domain of Sup35 forming dynamic aggregates. This prion-like nature governs known cellular functions of the TAR DNA-binding protein-43, including subcellular localisation and exon skipping of the cystic fibrosis transmembrane conductance regulator. Significantly, mutants with a failure to engage in prion-like interactions are processed into an ~24-kDa C-terminal fragment of the TAR DNA-binding protein-43. The estimated cleavage site of degraded TAR DNA-binding protein-43 fragments corresponds to the pathological cleavage site identified in patients with the TAR DNA-binding protein-43 proteinopathies. Consistently, epigallocatechin gallate constrains prion-like interactions, attenuating pathological-like degradation. Thus, the native folding of TAR DNA-binding protein-43 C terminus acts as a guardian of pathogenesis, which is directly associated with loss-of-function.
TAR DNA 结合蛋白-43 的降解、错误折叠的 C 端与广泛的神经退行性疾病有关，特别是额颞叶变性伴泛素阳性包涵体和肌萎缩侧索硬化症。然而，TAR DNA 结合蛋白-43 的病理性切割的确切机制仍不清楚。在这里，我们表明 TAR DNA 结合蛋白-43 的 C 端蛋白与自身或与细胞折叠的酵母 Sup35 的朊病毒结构域物理相互作用，形成动态聚集体。这种类朊病毒性质控制着 TAR DNA 结合蛋白-43 的已知细胞功能，包括囊性纤维化跨膜电导调节剂的亚细胞定位和外显子跳跃。重要的是，不能进行类朊病毒相互作用的突变体被加工成 TAR DNA 结合蛋白-43 的约 24 kDa C 端片段。降解的 TAR DNA 结合蛋白-43 片段的估计切割位点与 TAR DNA 结合蛋白-43 蛋白病患者中鉴定的病理性切割位点相对应。一致地，表没食子儿茶素没食子酸酯限制类朊病毒相互作用，减弱病理性降解。因此，TAR DNA 结合蛋白-43 C 端的天然折叠充当发病机制的守护者，与功能丧失直接相关。
