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A Zn-dependent structural transition of SOD1 modulates its ability to undergo phase separation
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-11-23 , DOI: 10.15252/embj.2022111185
Bidisha Das 1, 2 , Sumangal Roychowdhury 1 , Priyesh Mohanty 3 , Azamat Rizuan 3 , Joy Chakraborty 4 , Jeetain Mittal 3 , Krishnananda Chattopadhyay 1, 2
Affiliation  

The misfolding and mutation of Cu/Zn superoxide dismutase (SOD1) is commonly associated with amyotrophic lateral sclerosis (ALS). SOD1 can accumulate within stress granules (SGs), a type of membraneless organelle, which is believed to form via liquid–liquid phase separation (LLPS). Using wild-type, metal-deficient, and different ALS disease mutants of SOD1 and computer simulations, we report here that the absence of Zn leads to structural disorder within two loop regions of SOD1, triggering SOD1 LLPS and amyloid formation. The addition of exogenous Zn to either metal-free SOD1 or to the severe ALS mutation I113T leads to the stabilization of the loops and impairs SOD1 LLPS and aggregation. Moreover, partial Zn-mediated inhibition of LLPS was observed for another severe ALS mutant, G85R, which shows perturbed Zn-binding. By contrast, the ALS mutant G37R, which shows reduced Cu-binding, does not undergo LLPS. In addition, SOD1 condensates induced by Zn-depletion exhibit greater cellular toxicity than aggregates formed by prolonged incubation under aggregating conditions. Overall, our work establishes a role for Zn-dependent modulation of SOD1 conformation and LLPS properties that may contribute to amyloid formation.

中文翻译:


SOD1 的 Zn 依赖性结构转变调节其进行相分离的能力



铜/锌超氧化物歧化酶 (SOD1) 的错误折叠和突变通常与肌萎缩侧索硬化症 (ALS) 相关。 SOD1 可以在应激颗粒 (SG) 内积聚,应激颗粒是一种无膜细胞器,据信是通过液-液相分离 (LLPS) 形成的。使用 SOD1 的野生型、金属缺乏型和不同的 ALS 疾病突变体以及计算机模拟,我们在此报告,Zn 的缺失会导致 SOD1 的两个环区域内的结构紊乱,从而触发 SOD1 LLPS 和淀粉样蛋白的形成。将外源 Zn 添加到无金属 SOD1 或严重的 ALS 突变 I113T 中会导致环的稳定并损害 SOD1 LLPS 和聚集。此外,在另一种严重的 ALS 突变体 G85R 中观察到 LLPS 的部分 Zn 介导的抑制,该突变体显示出 Zn 结合受到干扰。相比之下,显示铜结合减少的 ALS 突变体 G37R 不会经历 LLPS。此外,与在聚集条件下长时间孵育形成的聚集体相比,缺锌诱导的 SOD1 缩合物表现出更大的细胞毒性。总体而言,我们的工作确立了 SOD1 构象和 LLPS 特性的锌依赖性调节的作用,这可能有助于淀粉样蛋白的形成。
更新日期:2022-11-23
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