Physics of active emulsions

Weber, Christoph A.; Zwicker, David; Jülicher, Frank; Lee, Chiu Fan

doi:10.1088/1361-6633/ab052b

Cited by 258 publications

(339 citation statements)

References 184 publications

(331 reference statements)

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“…Our findings also suggest that thermodynamic forces drive phase-separation during PFK-1.1 condensation. We note, however, that we also observed in vivo non-equilibrium properties to PFK-1.1 localization, which are likely the result of the interplay between cell biological regulatory mechanisms and phase separated condensates (what has been called "active emulsions" (Weber et al, 2019)). For example, we observed the exchange of material resulting, not in Ostwald ripening as would be predicted from thermodynamic equilibrium, but instead in similarly-sized adjacent condensates.…”

Section: Discussionmentioning

confidence: 61%

“…Instead, the exchange of material reached a dynamic equilibrium between adjacent condensates as they approached similar fluorescence levels (Figures 4E, 4F, and Movie 5). The observed in vivo dynamics between adjacent condensates could be because of occlusion of puncta in the tube-like geometry of the neurite from active cellular processes that drive the formation of two similar condensates (Berry et al, 2018;Weber et al, 2019), or because of other unidentified phenomena. Importantly, the exchange of material between adjacent clusters is consistent with liquid-like behaviors of the PFK-1.1 condensates.…”

Section: Pfk-11 Condensates Exhibit Liquid-like Behaviorsmentioning

confidence: 99%

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The Glycolytic Protein Phosphofructokinase Dynamically Relocalizes into Subcellular Compartments with Liquid-like Properties in vivo

Jang

Zhao

Lagoy

et al. 2019

Preprint

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While much is known about the biochemical regulation of glycolytic enzymes, less is understood about how they are organized inside cells. Here we built a hybrid microfluidic-hydrogel device for use in Caenorhabditis elegans to systematically examine and quantify the dynamic subcellular localization of the rate-limiting enzyme of glycolysis, phosphofructokinase-1/PFK-1.1. We determine that endogenous PFK-1.1 localizes to distinct, tissue-specific subcellular compartments in vivo. In neurons, PFK-1.1 is diffusely localized in the cytosol, but capable of dynamically forming phase-separated condensates near synapses in response to energy stress from transient hypoxia. Restoring animals to normoxic conditions results in the dispersion of PFK-1.1 in the cytosol, indicating that PFK-1.1 reversibly organizes into biomolecular condensates in response to cues within the cellular environment. PFK-1.1 condensates exhibit liquid-like properties, including spheroid shapes due to surface tension, fluidity due to deformations, and fast internal molecular rearrangements. Prolonged conditions of energy stress during sustained hypoxia alter the biophysical properties of PFK-1.1 in vivo, affecting its viscosity and mobility within phase-separated condensates. PFK-1.1's ability to form tetramers is critical for its capacity to form condensates in vivo, and heterologous self-association domain such as cryptochrome 2 (CRY2) is sufficient to constitutively induce the formation of PFK-1.1 condensates. PFK-1.1 condensates do not correspond to stress granules and might represent novel metabolic subcompartments. Our studies indicate that glycolytic protein PFK-1.1 can dynamically compartmentalize in vivo to specific subcellular compartments in response to acute energy stress via multivalency as phase-separated condensates.

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Section: Discussionmentioning

confidence: 61%

Section: Pfk-11 Condensates Exhibit Liquid-like Behaviorsmentioning

confidence: 99%

The Glycolytic Protein Phosphofructokinase Dynamically Relocalizes into Subcellular Compartments with Liquid-like Properties in vivo

Jang

Zhao

Lagoy

et al. 2019

Preprint

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“…phosphorylation, drives the transition between an interacting and a non-interacting protein species. In (Weber et al, 2019), the enrichment-inhibition model and the localization-induction model correspond to externally and internally maintained condensates, respectively. We clarified a crucial assumption, the differential enrichment of the kinase, phosphatase, or ATP (Patel et al, 2017) inside and outside of condensates for efficient size regulation.…”

Section: Related Theoretical Workmentioning

confidence: 99%

Mechanisms of active regulation of biomolecular condensates

Soeding

Zwicker

Sohrabi-Jahromi

et al. 2019

Preprint

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Liquid-liquid phase separation is a key organizational principle in eukaryotic cells, on par with intracellular membranes. It allows cells to concentrate specific proteins into condensates, increasing reaction rates and achieving switch-like regulation. However, it is unclear how cells trigger condensate formation or dissolution and regulate their sizes. We predict from first principles two mechanisms of active regulation by post-translational modifications such as phosphorylation: In enrichment-inhibition, the regulating modifying enzyme enriches in condensates and the modifications of proteins inhibit their interactions. Stress granules, Cajal bodies, P granules, splicing speckles, and synapsin condensates obey this model. In localization-induction, condensates form around an immobilized modifying enzyme, whose modifications strengthen protein interactions. Spatially targeted condensates formed during transmembrane signaling, microtubule assembly, and actin polymerization conform to this model. The two models make testable predictions that can guide studies into the many emerging roles of biomolecular condensates. Eukaryotic cells contain numerous types of mem-1 braneless organelles, which contain between a few 2 and thousands of protein and RNA species that are 3 highly enriched in comparison to the surrounding nu-4 cleoplasm or cytoplasm. These biomolecular conden-5 sates are held together by weak, multivalent and highly 6 collaborative interactions, often between intrinsically 7 54 active promoters. Here, we propose two active mecha-55 nisms used by cells for these purposes.56 Phase separation and condensate size behaviour 57 To keep the model simple, we consider only one type of 58 condensate protein. In the dilute regime below the sat-59 1 Cellular control of liquid droplet formation, size, and localization • July 5, 2019 Figure 1: Phase separation and condensate droplet size behaviour. A When protein-protein and solvent-solventinteractions are more favorable than protein-solvent interactions, demixing into two phases can occur, a dilute phase with low protein concentration c out and a dense phase with high concentration c in . This happens when the sum of free energies of the two phases is lower (tip of blue arrow) than the energy of the single phase (base of blue arrow) . B c out is the limiting concentration for infinite condensate droplet radius R. The concentration on the outside of a condensate of radius R is larger the smaller the condensate is (green double-headed arrows), as it cannot hold on to its proteins as well as large ones. This leads to a concentration gradient (∇concentration), which fuels a diffusive flux from small to large condensates (wiggly arrows). (l c is a measure of interaction strength between proteins in comparison to the solvent.) C As a result, condensates below a radius R crit will shrink and larger ones will grow. uration protein concentration c out , condensate droplets 60 cannot form ( Figure 1A). Above c out , in the phase sepa-61 ration regime, condensates can be stable...

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“…Chemical and enzymatic reactions facilitate the continually dynamic state of cells. Here we are interested in active coacervates, which are coacervates with external or internal energy supply (see Berry et al 13 and Weber et al 14 for recent reviews). Active coacervate systems have been studied by Alexander Oparin, who hypothesized that such systems provided a stepping stone for the origin of life on earth [15][16][17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Non-spherical coacervate shapes in an enzyme driven active system

Spoelstra

Sluis

Dogterom

et al. 2019

Preprint

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Coacervates are polymer-rich droplets that form through liquid-liquid phase separation in polymer solutions. Liquid-liquid phase separation and coacervation have recently been shown to play an important role in the organization of biological systems. Such systems are highly dynamic and under continuous influence of enzymatic and chemical processes. However, it is still unclear how enzymatic and chemical reactions affect the coacervation process. Here, we present and characterize a system of enzymatically active coacervates containing spermine, RNA, free nucleotides, and the template independent RNA (de)polymerase PNPase. We find that these RNA coacervates display transient non-spherical shapes, and we systematically study how PNPase concentration, UDP concentration and temperature affect coacervate morphology. Furthermore, we show that PNPase localizes predominantly into the coacervate phase and that its depolymerization activity in high-phosphate buffer causes coacervate degradation. Our observations of non-spherical coacervate shapes may have broader implications for the relationship between (bio-)chemical activity and coacervate biology.

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Physics of active emulsions

Cited by 258 publications

References 184 publications

The Glycolytic Protein Phosphofructokinase Dynamically Relocalizes into Subcellular Compartments with Liquid-like Properties in vivo

The Glycolytic Protein Phosphofructokinase Dynamically Relocalizes into Subcellular Compartments with Liquid-like Properties in vivo

Mechanisms of active regulation of biomolecular condensates

Non-spherical coacervate shapes in an enzyme driven active system

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