Controlling interfacial protein adsorption, desorption and aggregation in biomolecular condensates
The aggregation of amyloidogenic proteins is linked to age-related diseases. The presence of interfaces can affect their aggregation mechanism, often speeding up aggregation. -Synuclein (Syn) can adsorb to biomolecular condensates, leading to heterogenous nucleation and faster aggregation. Understanding the mechanism underlying localization of amyloidogenic proteins at condensate interfaces is crucial for developing strategies to prevent or reverse their binding. We show that Syn localization to the surface of peptide-based heterotypic condensates is an adsorption process governed by the proteins condensate-amphiphilic nature. Adsorption occurs in multiple layers and levels off at micromolar concentrations. Based on these findings, we design three strategies to modulate Syn accumulation: (i) addition of biomolecules that decrease the condensate {zeta}-potential, such as NTPs and RNA, (ii) competitive adsorption of proteins targeting the condensate interface, such as G3BP1, DDX4-YFP, EGFP-NPM1, Hsp70, Hsc70, and (iii) preferential adsorption of Syn to membranes. Removing Syn from the condensate interface slows aggregation, highlighting potential cellular control over protein adsorption and implications for therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/619145v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@159b012org.highwire.dtl.DTLVardef@1369671org.highwire.dtl.DTLVardef@ced970org.highwire.dtl.DTLVardef@2578b0_HPS_FORMAT_FIGEXP M_FIG C_FIG