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Multivalent Proteins Rapidly and Reversibly Phase-Separate upon Osmotic Cell Volume Change.

ABSTRACT: Processing bodies (PBs) and stress granules (SGs) are prominent examples of subcellular, membraneless compartments that are observed under physiological and stress conditions, respectively. We observe that the trimeric PB protein DCP1A rapidly (within ∼10 s) phase-separates in mammalian cells during hyperosmotic stress and dissolves upon isosmotic rescue (over ∼100 s) with minimal effect on cell viability even after multiple cycles of osmotic perturbation. Strikingly, this rapid intracellular hyperosmotic phase separation (HOPS) correlates with the degree of cell volume compression, distinct from SG assembly, and is exhibited broadly by homo-multimeric (valency ≥ 2) proteins across several cell types. Notably, HOPS sequesters pre-mRNA cleavage factor components from actively transcribing genomic loci, providing a mechanism for hyperosmolarity-induced global impairment of transcription termination. Our data suggest that the multimeric proteome rapidly responds to changes in hydration and molecular crowding, revealing an unexpected mode of globally programmed phase separation and sequestration.

SUBMITTER: Jalihal AP

PROVIDER: S-EPMC7502480 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-08-14 | GSE156228 | GEO

Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

Project description:Processing bodies (PBs) and stress granules (SGs) are prominent examples of subcellular, membrane-less compartments that are observed under physiological and stress conditions, respectively. We observe that the trimeric PB protein DCP1A rapidly (within ~10 s) phase-separates in mammalian cells during hyperosmotic stress and dissolves upon isosmotic rescue (over ~100 s) with minimal impact on cell viability even after multiple cycles of osmotic perturbation. Strikingly, this rapid intracellular hyperosmotic phase separation (HOPS) correlates with the degree of cell volume compression, distinct from SG assembly, and is exhibited broadly by homo-multimeric (valency ≥ 2) proteins across several cell types. Notably, HOPS sequesters pre-mRNA cleavage factor components from actively transcribing genomic loci, providing a mechanism for hyperosmolarity-induced global impairment of transcription termination. Together, our data suggest that the multimeric proteome rapidly responds to changes in hydration and molecular crowding, revealing an unexpected mode of globally programmed phase separation and sequestration that adapts the cell to volume change.

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Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change [ChIP-seq]

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Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change [RNA-seq]

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Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

Project description:Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

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Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

Project description:Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

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Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change [RNA-seq]

Project description:Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change [RNA-seq]

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Project description:Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change [ChIP-seq]

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Phase transitions in the assembly of multivalent signalling proteins.

Project description:Cells are organized on length scales ranging from ångström to micrometres. However, the mechanisms by which ångström-scale molecular properties are translated to micrometre-scale macroscopic properties are not well understood. Here we show that interactions between diverse synthetic, multivalent macromolecules (including multi-domain proteins and RNA) produce sharp liquid-liquid-demixing phase separations, generating micrometre-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to the valency of the interacting species. In the case of the actin-regulatory protein called neural Wiskott-Aldrich syndrome protein (N-WASP) interacting with its established biological partners NCK and phosphorylated nephrin, the phase transition corresponds to a sharp increase in activity towards an actin nucleation factor, the Arp2/3 complex. The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. The widespread occurrence of multivalent systems suggests that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.

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Project description:Many biomolecular condensates form via spontaneous phase transitions that are driven by multivalent proteins. These molecules are biological instantiations of associative polymers that conform to a so-called stickers-and-spacers architecture. The stickers are protein-protein or protein-RNA interaction motifs and / or domains that can form reversible, non-covalent crosslinks with one another. Spacers are interspersed between stickers and their preferential interactions with solvent molecules determine the cooperativity of phase transitions. Here, we report the development of an open source computational engine known as LASSI (LAttice simulation engine for Sticker and Spacer Interactions) that enables the calculation of full phase diagrams for multicomponent systems comprising of coarse-grained representations of multivalent proteins. LASSI is designed to enable computationally efficient phenomenological modeling of spontaneous phase transitions of multicomponent mixtures comprising of multivalent proteins and RNA molecules. We demonstrate the application of LASSI using simulations of linear and branched multivalent proteins. We show that dense phases are best described as droplet-spanning networks that are characterized by reversible physical crosslinks among multivalent proteins. We connect recent observations regarding correlations between apparent stoichiometry and dwell times of condensates to being proxies for the internal structural organization, specifically the convolution of internal density and extent of networking, within condensates. Finally, we demonstrate that the concept of saturation concentration thresholds does not apply to multicomponent systems where obligate heterotypic interactions drive phase transitions. This emerges from the ellipsoidal structures of phase diagrams for multicomponent systems and it has direct implications for the regulation of biomolecular condensates in vivo.

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