Valence and patterning of aromatic residues determine the phase behavior of prion-like domains

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6478; pp. 694 - 699
• Main Authors: Martin, Erik W, Holehouse, Alex S, Peran, Ivan, Farag, Mina, Incicco, J Jeremias, Bremer, Anne, Grace, Christy R, Soranno, Andrea, Pappu, Rohit V, Mittag, Tanja
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07.02.2020; AAAS
• Subjects: Agglomeration; Amino Acid Sequence; Amino acids; Climate; Computer simulation; Dilution; Domains; Heterogeneous Nuclear Ribonucleoprotein A1 - chemistry; Liquid phases; Magnetic Resonance Spectroscopy; NMR; Nuclear magnetic resonance; Phase separation; Phase Transition; Phenylalanine - chemistry; Prions - chemistry; Protein Domains; Residues; Resonance scattering; Scattering, Small Angle; Small angle X ray scattering; Spacers; Temperature dependence; Tyrosine - chemistry; X-Ray Diffraction; X-ray scattering
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaw8653

Prion-like domains (PLDs) can drive liquid-liquid phase separation (LLPS) in cells. Using an integrative biophysical approach that includes nuclear magnetic resonance spectroscopy, small-angle x-ray scattering, and multiscale simulations, we have uncovered sequence features that determine the overall phase behavior of PLDs. We show that the numbers (valence) of aromatic residues in PLDs determine the extent of temperature-dependent compaction of individual molecules in dilute solutions. The valence of aromatic residues also determines full binodals that quantify concentrations of PLDs within coexisting dilute and dense phases as a function of temperature. We also show that uniform patterning of aromatic residues is a sequence feature that promotes LLPS while inhibiting aggregation. Our findings lead to the development of a numerical stickers-and-spacers model that enables predictions of full binodals of PLDs from their sequences.