Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain

Murthy, Anastasia C.; Dignon, Gregory L.; Kan, Yelena; Zerze, Gül H.; Parekh, Sapun H.; Mittal, Jeetain; Fawzi, Nicolas L.

doi:10.1038/s41594-019-0250-x

Cited by 542 publications

(813 citation statements)

References 65 publications

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“…A second set of reports has suggested that LCDs within condensed droplets remain entirely disordered and dynamic [62][63][64][65] (Figure 2). These conclusions stem from solution NMR spectroscopy on pure dense phases.…”

Section: Structures Of Low Complexity Domains Studied In Dense Liquidmentioning

confidence: 99%

Molecular structure in biomolecular condensates

Mittag

2020

Current Opinion in Structural Biology

116

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Evidence accumulated over the past decade provides support for liquid-liquid phase separation as the mechanism underlying the formation of biomolecular condensates, which include not only "membraneless" organelles such as nucleoli and RNA granules, but additional assemblies involved in transcription, translation and signaling. Understanding the molecular mechanisms of condensate function requires knowledge of the structures of their constituents. Current knowledge suggests that structures formed via multivalent domain-motif interactions remain largely unchanged within condensates. Two different viewpoints exist regarding structures of disordered low-complexity domains within condensates; one argues that low-complexity domains remain largely disordered in condensates and their multivalency is encoded in short motifs called "stickers", while the other argues that the sequences form cross-b structures resembling amyloid fibrils. We review these viewpoints and highlight outstanding questions that will inform structure-function relationships for biomolecular condensates.

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Section: Structures Of Low Complexity Domains Studied In Dense Liquidmentioning

confidence: 99%

Molecular structure in biomolecular condensates

Mittag

2020

Current Opinion in Structural Biology

116

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“…We find that the “bona fide” heterochromatin proteins contain various segments of high hydrophobicity and with a high fraction of charged residues (Figs A–C and EV1A–E), which could potentially favour phase separation. These features may be hard to interpret however, since they may not be sufficient per se to drive liquid–liquid phase separation, as recently shown for the FUS low‐complexity domain . Overall, these analyses suggest that the “bona fide” heterochromatin proteins that we selected have additional features linked to the potential to phase separate.…”

Section: Resultsmentioning

confidence: 84%

Expression and phase separation potential of heterochromatin proteins during early mouse development

2019

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In most eukaryotes, constitutive heterochromatin is associated with H3K9me3 and HP1α. The latter has been shown to play a role in heterochromatin formation through liquid–liquid phase separation. However, many other proteins are known to regulate and/or interact with constitutive heterochromatic regions in several species. We postulate that some of these heterochromatic proteins may play a role in the regulation of heterochromatin formation by liquid–liquid phase separation. Indeed, an analysis of the constitutive heterochromatin proteome shows that proteins associated with constitutive heterochromatin are significantly more disordered than a random set or a full nucleome set of proteins. Interestingly, their expression begins low and increases during preimplantation development. These observations suggest that the preimplantation embryo is a useful model to address the potential role for phase separation in heterochromatin formation, anticipating exciting research in the years to come.

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“…In the present study, neutral beads and empty lattice sites do not interact energetically with other beads; other types of interactions could be included. Several different types of interactions are thought to contribute to IDP phase separation, including π-π stacking (i.e., interactions between aromatic residues), cation-π, dipole-dipole interactions and hydrogen bonding [10,47]. Hydrophobic attraction is a key stabilizing force in protein folding [48] and aggregation [49], and it can also play a role in liquid-liquid phase separation [50].…”

Section: Discussionmentioning

confidence: 99%

Phase behavior of blocky charge lattice polymers: Crystals, liquids, sheets, filaments, and clusters

2019

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Motivated by the idea that intrinsically disordered proteins (IDPs) condense into liquid-like droplets within cells, we carry out Monte Carlo simulations of a polymer lattice model to study the relationship between charge patterning and phase separation. Polymer chains containing neutral, positively charged and negatively charged monomers are placed on a cubic lattice. Only nearest neighbor interactions between charges are considered. We determine the phase diagram for a systematically varied set of sequences. We observe homogeneous fluids, liquid condensation, cluster phases, filaments, and crystal states. Of the six sequences we study, three form crystals at low temperatures. The other three sequences, which have lower charge densities, instead collapse into gel-like networks or unconnected finite clusters. Longer neutral patches along the sequence sterically limit the size and shape of low-energy structures, which is analogous to the effect of charge or limited valence in attractive colloids. Only one sequence clearly exhibits liquid behavior; this sequence has a reduced tendency to individually fold and crystallize compared to others of similar charge density and draws parallels to real IDP behavior. arXiv:1912.04322v1 [cond-mat.soft]

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Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain

Cited by 542 publications

References 65 publications

Molecular structure in biomolecular condensates

Molecular structure in biomolecular condensates

Expression and phase separation potential of heterochromatin proteins during early mouse development

Phase behavior of blocky charge lattice polymers: Crystals, liquids, sheets, filaments, and clusters

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