posted on 2021-11-18, 00:44authored byNirnay Samanta, Sara S. Ribeiro, Mailin Becker, Emeline Laborie, Roland Pollak, Stepan Timr, Fabio Sterpone, Simon Ebbinghaus
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.