De novo peptides that induce the liquid-liquid phase separation of α-synuclein

Abstract Liquid-liquid phase separation (LLPS) of protein that leads to formation of membrane-less organelles is a critical event to many processes in the cell. Recently, some disease-related proteins, such as α-synuclein (αSyn), were found to undergo LLPS before their formation of amyloid fibrils. However, the progress towards controlling LLPS has been limited, and there has been no emerging engineered de novo molecules to induce and modulate the LLPS of targeted proteins. Here we report peptides that efficiently induce the LLPS of αSyn, discovered by the RaPID (random non-standard peptides integrated discovery) system. These peptides are able to co-localize with αSyn in liquid droplets via heterotypic interacting with the N- and C-terminal regions of αSyn. Our study demonstrates the capacity of target-specific peptides to control LLPS and modulate the physical nature of condensate. Thus, these peptides could be a unique tool to gain deeper insights in the LLPS-mediated amyloid formation.