Interplay of folded domains and the disordered low-complexity domain in mediating hnRNPA1 phase separation

Abstract Liquid–liquid phase separation underlies the membrane-less compartmentalization of cells. Intrinsically disordered low-complexity domains (LCDs) often mediate separation, but how their behavior is modulated by folded incompletely understood. Here, we interrogate interplay between and RNA-binding protein hnRNPA1. The LCD hnRNPA1 sufficient for mediating in vitro. However, show that RRM a solubility-tag modify behavior, even absence RNA. Notably, presence reverses salt dependence driving force relative to alone. Small-angle X-ray scattering experiments coarse-grained MD simulations interacts transiently with RRMs and/or salt-sensitive manner, providing mechanistic explanation observed salt-dependent separation. These data point two effects from domains: (i) electrostatically-mediated interactions compact contribute (ii) increased solubility at higher ionic strengths mediated domains. can on solution conditions obscure signatures physicochemical underlying