Misfolded proteins share a common capacity in disrupting LLPS organizing membrane-less organelles

Profilin-1 mutants cause ALS by gain of toxicity but the underlying mechanism remains unknown. Here we showed that three PFN1 mutants have differential capacity in disrupting dynamics of FUS liquid droplets underlying the formation of stress granules (SGs). Subsequently we extensively characterized conformations, dynamics and hydrodynamic properties of C71G-PFN1, FUS droplets and their interaction by NMR spectroscopy. C71G-PFN1 co-exists between the folded (55.2%) and unfolded (44.8%) states undergoing exchanges at 11.7 Hz, while its unfolded state non-specifically interacts with FUS droplets. Results together lead to a model for dynamic droplets to recruit misfolded proteins, which functions seemingly at great cost: simple accumulation of misfolded proteins within liquid droplets is sufficient to reduce their dynamics. Further aggregation of misfolded proteins within droplets might irreversibly disrupt/destroy structures and dynamics of droplets, as increasingly observed on SGs, an emerging target for various neurodegenerative diseases. Therefore, our study implies that other misfolded proteins might also share the capacity in disrupting LLPS.