Expanding the molecular grammar of polar residues and arginine in FUS phase separation

Abstract

A molecular grammar governing low-complexity prion-like domain phase separation (PS) has identified tyrosine and arginine as primary drivers via aromatic–aromatic and aromatic–arginine interactions. Here we show that additional residues and contacts contribute to PS, highlighting the need to include these contributions in PS theories and models. Tyrosine and arginine make important contacts beyond tyrosine–tyrosine and tyrosine–arginine, including arginine–arginine contacts. Among polar residues, glutamine contributes to PS with sequence and position specificity, contacting tyrosine, arginine and other residues, both before PS and in condensed phases. The flexibility of glycine enhances PS by allowing favorable contacts between adjacent residues and inhibits the liquid-to-solid transition. Polar residues also make sequence-specific contributions to liquid-to-solid transition, with serine positions linked to the formation of an amyloid-core structure by the FUS low-complexity domain. Hence, an extended molecular grammar expands the role of arginine and polar residues in prion-like domain protein PS and reveals the position dependence of residue contribution to solidification. This study expands the molecular grammar of FUS, identifying tyrosine, arginine and glutamine as key drivers of phase separation and showing that flexibility from glycine enhances phase separation. Sequence and position affect the contributions of specific residues to phase separation and aggregation.