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, in vitro and by simulation. We find that irrespective of aggregation the folding stability determines the association of SOD1 with SGs in cells. In vitro and in silico 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.

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

Institute of Physical and Theoretical Chemistry TU Braunschweig Rebenring 56 D 38106 Braunschweig Germany

J Heyrovský Institute of Physical Chemistry Czech Academy of Sciences Dolejskova 2155 3 Prague 8 182 23 Czech Republic

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Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant