Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore.
Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore.
Biochem Biophys Res Commun. 2020 Apr 2;524(2):459-464. doi: 10.1016/j.bbrc.2020.01.122. Epub 2020 Jan 30.
TDP-43 inclusion is a pathological hallmark for ∼97% ALS and ∼45% FTD patients. So far, >50 ALS-causing mutations have been identified, most of which are hosted by the intrinsically-disordered prion-like domain. The D169G mutation is the only one within the well-folded RRM1 domain, which, however, induces no significant change of the crystal structure and even slightly enhances the thermodynamic stability. Therefore, the mechanism for D169G to enhance the cytotoxicity remains elusive. Here by NMR, we reveal for the first time: 1) D169G does trigger significant dynamic changes for a cluster of residues. 2) Very unexpectedly, D169G disrupts the ATP-binding capacity of RRM1 although the ATP-binding pocket is on the back side of the mutation site. Taken together with our previous results, the current study provides a potential mechanism to rationalize enhancement of the TDP-43 cytotoxicity by D169G and highlights again the key roles of ATP in neurodegenerative diseases and ageing.
TDP-43 包含物是大约 97%的 ALS 和大约 45%的 FTD 患者的病理标志。到目前为止，已经鉴定出超过 50 种导致 ALS 的突变，其中大多数位于固有无序的朊病毒样结构域内。D169G 突变是唯一位于充分折叠的 RRM1 结构域内的突变，但它不会引起晶体结构的显著变化，甚至略微增强热力学稳定性。因此，D169G 增强细胞毒性的机制仍然难以捉摸。在这里，我们首次通过 NMR 揭示：1）D169G 确实会引发一组残基的显著动态变化。2）非常出乎意料的是，尽管 ATP 结合口袋位于突变位点的背面，D169G 会破坏 RRM1 的 ATP 结合能力。与我们之前的结果相结合，本研究为合理化 D169G 增强 TDP-43 细胞毒性提供了一个潜在的机制，并再次强调了 ATP 在神经退行性疾病和衰老中的关键作用。
