Liquid-liquid phase separation (LLPS) is now recognized as a mechanism by which cells organize contents in membraneless organelles and control diverse biological functions. Although intrinsically disordered regions (IDRs) are often viewed as main drivers of LLPS, the precise molecular determinants remain unclear. To explore whether folded domains contribute to condensate formation, we investigated the small ubiquitin-like modifier protein, SUMO1. We discovered that SUMO1 on its own undergoes rapid phase separation at physiological conditions, forming micrometer-sized and liquid-like condensates. Spectroscopic measurements revealed time-dependent SUMO1 structural rearrangements and subsequent aggregation in the condensates. A SUMO1 variant lacking the N-terminal disordered region also formed condensates, revealing that a folded domain alone is sufficient to drive condensate formation. Extending from this work, we now explore small-molecule cellular factors (metal ions, metabolites) as well as intra-molecular aspects (missense mutations, truncations, and post-translational modifications) in modulating condensate formation, and maturation to amyloids, of the Parkinson’s disease protein, α-synuclein.
Arora et al. (Sun,) studied this question.