Tan Cheng, Niitsu Ai, Sugita Yuji
Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Hyogo 650-0047, Japan.
Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan.
JACS Au. 2023 Feb 24;3(3):834-848. doi: 10.1021/jacsau.2c00646. eCollection 2023 Mar 27.
Biomolecular condensation is involved in various cellular processes; therefore, regulation of condensation is crucial to prevent deleterious protein aggregation and maintain a stable cellular environment. Recently, a class of highly charged proteins, known as heat-resistant obscure (Hero) proteins, was shown to protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero proteins protect other proteins from aggregation remain unknown. In this study, we performed multiscale molecular dynamics (MD) simulations of Hero11, a Hero protein, and the C-terminal low-complexity domain (LCD) of the transactive response DNA-binding protein 43 (TDP-43), a client protein of Hero11, under various conditions to examine their interactions with each other. We found that Hero11 permeates into the condensate formed by the LCD of TDP-43 (TDP-43-LCD) and induces changes in conformation, intermolecular interactions, and dynamics of TDP-43-LCD. We also examined possible Hero11 structures in atomistic and coarse-grained MD simulations and found that Hero11 with a higher fraction of disordered region tends to assemble on the surface of the condensates. Based on the simulation results, we have proposed three possible mechanisms for Hero11's regulatory function: (i) In the dense phase, TDP-43-LCD reduces contact with each other and shows faster diffusion and decondensation due to the repulsive Hero11-Hero11 interactions. (ii) In the dilute phase, the saturation concentration of TDP-43-LCD is increased, and its conformation is relatively more extended and variant, induced by the attractive Hero11-TDP-43-LCD interactions. (iii) Hero11 on the surface of small TDP-43-LCD condensates can contribute to avoiding their fusion due to repulsive interactions. The proposed mechanisms provide new insights into the regulation of biomolecular condensation in cells under various conditions.
生物分子凝聚参与了各种细胞过程；因此，对凝聚的调控对于防止有害的蛋白质聚集和维持稳定的细胞环境至关重要。最近，一类被称为耐热模糊（Hero）蛋白的高电荷蛋白被证明可以保护其他客户蛋白免受病理性聚集。然而，Hero蛋白保护其他蛋白免于聚集的分子机制仍然未知。在本研究中，我们在各种条件下对Hero蛋白Hero11以及Hero11的客户蛋白——转录激活反应DNA结合蛋白43（TDP-43）的C端低复杂性结构域（LCD）进行了多尺度分子动力学（MD）模拟，以研究它们之间的相互作用。我们发现Hero11渗透到由TDP-43的LCD（TDP-43-LCD）形成的凝聚物中，并诱导TDP-43-LCD的构象、分子间相互作用和动力学发生变化。我们还在原子尺度和粗粒度MD模拟中研究了Hero11可能的结构，发现无序区域比例较高的Hero11倾向于聚集在凝聚物表面。基于模拟结果，我们提出了Hero11调控功能的三种可能机制：（i）在致密相中，由于Hero11-Hero11之间的排斥相互作用，TDP-43-LCD相互接触减少，扩散和去凝聚速度加快。（ii）在稀释相中，由于Hero11-TDP-43-LCD之间的吸引相互作用，TDP-43-LCD的饱和浓度增加，其构象相对更伸展且多变。（iii）小的TDP-43-LCD凝聚物表面的Hero11由于排斥相互作用有助于避免它们的融合。所提出的机制为各种条件下细胞中生物分子凝聚的调控提供了新的见解。
