Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions

• Published in: Nature communications Vol. 14; no. 1; pp. 5527 - 16
• Main Authors: Farag, Mina, Borcherds, Wade M., Bremer, Anne, Mittag, Tanja, Pappu, Rohit V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.09.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 132/124; 631/57/2269; 639/766/747; 82/80; 82/83; Biomolecular Condensates; Complexity; Condensates; Electrostatic properties; Humanities and Social Sciences; Mixtures; multidisciplinary; Percolation; Phase separation; Prion protein; Prions; Proteins; RNA-binding protein; Science; Science (multidisciplinary); Simulation; Static Electricity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41274-x

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via phase separation coupled to percolation. Intracellular condensates often encompass numerous distinct proteins with PLCDs. Here, we combine simulations and experiments to study mixtures of PLCDs from two RNA-binding proteins, hnRNPA1 and FUS. Using simulations and experiments, we find that 1:1 mixtures of A1-LCD and FUS-LCD undergo phase separation more readily than either of the PLCDs on their own due to complementary electrostatic interactions. Tie line analysis reveals that stoichiometric ratios of different components and their sequence-encoded interactions contribute jointly to the driving forces for condensate formation. Simulations also show that the spatial organization of PLCDs within condensates is governed by relative strengths of homotypic versus heterotypic interactions. We uncover rules for how interaction strengths and sequence lengths modulate conformational preferences of molecules at interfaces of condensates formed by mixtures of proteins. Mixtures of prion-like low complexity domains (PLCDs) are found in condensates such as stress granules. In this work, the authors report how the interplay between homotypic and heterotypic interactions contributes to condensate formation by mixtures of PLCDs.