A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins

By Jie Wang, Jeong-Mo Choi, Alex S. Holehouse, Hyun O. Lee, Xiaojie Zhang, Marcus Jahnel, Shovamayee Maharana, Régis P. Lemaitre, Andrei Pozniakovsky, D. Drechsel and 4 more. Cell, 2018

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SUMMARY Proteins such as FUS phase separate to form liquid-like condensates that can harden into less dynamic structures. However, how these properties emerge from the collective interactions of many amino acids remains largely unknown. Here, we use extensive mutagenesis to identify a sequence-encoded molecular grammar underlying the driving forces for phase separation of proteins of the FUS family, and test aspects of this grammar in cells. Phase separation is governed primarily by multivalent interactions amongst tyrosine residues from prion-like domains and arginine residues from RNA binding domains, which are modulated by negatively charged residues. Glycine residues enhance the fluidity, whereas glutamine and serine residues promote hardening. We develop a model to show that the measured saturation concentrations of phase separation are inversely proportional to the product of the numbers of arginine and tyrosine residues. These results suggest it is possible to predict phase separation properties based on amino acid sequence.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e0f2ffc353971d304cf5d312c625378e85ae4ee9

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Citations in the corpus

Physical Principles Underlying the Complex Biology of Intracellular Phase Transitions (2020, background): “(170) and assume that εAA = εBB = 0 and εAB < 0.”
Competing protein-RNA interaction networks control multiphase intracellular organization (2020, positive): “Notwithstanding tremendous attention focused on self-associating IDRs in LLPS (Elbaum-Garfinkle et al., 2015; Kato et al., 2012; Lin et al., 2015; Molliex et al., 2015; Nott et al., 2015; Patel et al., 2015; Wang et al., 2018), studies have shown that both ODs and RBDs have essential roles in conden”
Liquid-Liquid Phase Separation in Disease. (2019, background): “between arginines and aromatic residues, which drive condensation of FUS (127, 152).”
Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy (2021, methodology): “For the A1-LCD wild type, this can be 8)) for selected residue pairs (Supplementary Table 1 presents the one-letter amino acid codes) in the mpipi ( a ), KH ( b ), HPS-KR ( c ), HPS + cation– π (ii) ( d ), Fb-HPS ( e ) and HPS-Urry ( f ) models.”