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

By E. Martin, Alex S. Holehouse, I. Peran, M. Farag, J. J. Incicco, Anne Bremer, C. Grace, Andrea Soranno, Rohit V. Pappu, Tanja Mittag. Science, 2020

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Not too sticky There is increasing evidence for a role of liquid-liquid phase separation (LLPS) in many cellular processes. Many proteins that undergo LLPS include prionlike domains (PLDs), which are enriched in polar amino acids and often interspersed with aromatic residues. Combining experimental data with simulations, Martin et al. quantified concentrations of PLDs in coexisting dilute and dense phases as a function of temperature and show that the phase behavior is determined by the number of aromatic residues and their patterning, with uniform patterning of aromatic residues promoting LLPS and inhibiting aggregation. They developed a sticker-and-spacers model that can predict the phase behavior of PLDs on the basis of their sequence. Science, this issue p. 694 A stickers-and-spacers model reproduces experimentally measured sequence-specific phase diagrams of prion-like domains. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/78254dad717ce781744182adc6e7afc3bd6fead4

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