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. 2018 Oct 2;504(2):545-551. doi: 10.1016/j.bbrc.2018.09.014. Epub 2018 Sep 8.
ATP is the universal energy currency but mysteriously its cellular concentration is much higher than that needed for providing energy. Recently ATP was decoded to act as a hydrotrope to dissolve liquid-liquid phase separation (LLPS) of FUS whose aggregation leads to ALS/FTD. By DIC microscopy and NMR, here we characterized the effect of ATP on LLPS of FUS and its N-/C-terminal domains. Very unexpectedly, we found that like nucleic acids, ATP enhances LLPS of FUS at low but dissolves at high concentrations. Intriguingly, ATP monotonically dissolves LLPS of NTD, while it induces LLPS of CTD at low but dissolves at high concentrations. Our study reveals for the first time that ATP can enhance LLPS most likely by behaving as a bivalent binder. Most importantly, our results imply that age-dependent reduction of ATP concentrations may not only result in decreasing its capacity in preventing protein aggregation, but also in enhancing aggregation.
ATP 是通用的能量货币，但令人费解的是，其细胞浓度远远高于提供能量所需的浓度。最近，ATP 被解码为一种水增溶物，可溶解 FUS 的液-液相分离 (LLPS)，其聚集导致 ALS/FTD。通过相差显微镜和 NMR，我们在这里表征了 ATP 对 FUS 及其 N-/C-末端结构域 LLPS 的影响。令人意外的是，我们发现与核酸类似，ATP 在低浓度下增强 FUS 的 LLPS，但在高浓度下溶解。有趣的是，ATP 单调地溶解 NTD 的 LLPS，而在低浓度下诱导 CTD 的 LLPS，但在高浓度下溶解。我们的研究首次揭示，ATP 可以通过充当二价配体来增强 LLPS。最重要的是，我们的结果表明，随着年龄的增长，ATP 浓度的降低不仅可能导致其预防蛋白质聚集的能力降低，而且还可能增强聚集。
