Institute of Physical and Theoretical Chemistry, TU Braunschweig, Rebenring 56, D-38106 Braunschweig, Germany.
CNRS Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Université Paris Denis Diderot, Sorbonne Paris Cité, PSL Research University, 13 rue Pierre et Marie Curie, Paris 75005, France.
J Am Chem Soc. 2021 Dec 1;143(47):19909-19918. doi: 10.1021/jacs.1c09589. Epub 2021 Nov 17.
Stress granules (SGs) are among the most studied membraneless organelles that form upon heat stress (HS) to sequester unfolded, misfolded, or aggregated protein, supporting protein quality control (PQC) clearance. The folding states that are primarily associated with SGs, as well as the function of the phase separated environment in adjusting the energy landscapes, remain unknown. Here, we investigate the association of superoxide dismutase 1 (SOD1) proteins with different folding stabilities and aggregation propensities with condensates in cells, and by simulation. We find that irrespective of aggregation the folding stability determines the association of SOD1 with SGs in cells. and experiments however suggest that the increased flexibility of the unfolded state constitutes only a minor driving force to associate with the dynamic biomolecular network of the condensate. Specific protein-protein interactions in the cytoplasm in comparison to SGs determine the partitioning of folding states between the respective phases during HS.
应激颗粒（SGs）是研究最多的无膜细胞器之一，在热应激（HS）时形成，以隔离未折叠、错误折叠或聚集的蛋白质，支持蛋白质质量控制（PQC）清除。与 SGs 主要相关的折叠状态，以及相分离环境在调节能量景观方面的功能仍然未知。在这里，我们研究了超氧化物歧化酶 1（SOD1）蛋白与不同折叠稳定性和聚集倾向与细胞内凝聚物的关联，以及通过模拟。我们发现，无论聚集如何，折叠稳定性决定了 SOD1 在细胞中与 SG 的关联。然而，实验表明，未折叠状态的柔韧性增加仅构成与凝聚物的动态生物分子网络关联的次要驱动力。与 SG 相比，细胞质中特定的蛋白质-蛋白质相互作用决定了在 HS 期间折叠状态在相应相之间的分配。
