Wei Yuanyuan, Lim Liangzhong, Wang Lu, Song Jianxing
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
Biochem Biophys Res Commun. 2016 Apr 29;473(2):614-9. doi: 10.1016/j.bbrc.2016.03.158. Epub 2016 Apr 1.
TDP-43 inclusions have been found in ∼97% ALS as well as an increasing spectrum of other neurodegenerative diseases including Alzheimer's. TDP-43 contains an ubiquitin-like fold, two RRMs and a prion-like domain, but whether they interact with each other remains unknown due to being intrinsically aggregation-prone. Nevertheless, this knowledge is pivotal to understanding physiological functions and pathological roles of TDP-43. Here as facilitated by our previous discovery which allowed NMR characterization of TDP-43 and its five dissected fragments, we successfully decoded that TDP-43 does have dynamic inter-domain interactions, which are coordinated by the intrinsically-disordered prion-like domain. Thus, TDP-43 appears to undergo conformational exchanges between "closed" and "open" states which are needed for its functions. Our study thus offers a mechanism by which cellular processes might control TDP-43 physiology and proteinopathy by mediating its inter-domain interactions.
在约97%的肌萎缩侧索硬化症（ALS）以及包括阿尔茨海默病在内的越来越多的其他神经退行性疾病中都发现了TDP-43包涵体。TDP-43包含一个泛素样折叠、两个RNA识别基序（RRMs）和一个朊病毒样结构域，但由于其本身易于聚集，它们之间是否相互作用仍不清楚。然而，这一知识对于理解TDP-43的生理功能和病理作用至关重要。在此，得益于我们之前的发现，该发现使得对TDP-43及其五个切割片段进行核磁共振（NMR）表征成为可能，我们成功解析出TDP-43确实存在动态的结构域间相互作用，这种相互作用由内在无序的朊病毒样结构域协调。因此，TDP-43似乎在“闭合”和“开放”状态之间进行构象交换，而这是其功能所必需的。我们的研究因此提供了一种机制，通过该机制细胞过程可能通过介导TDP-43的结构域间相互作用来控制其生理功能和蛋白病变。
