Phase Transition of RNA-protein Complexes into Ordered Hollow Condensates

Alshareedah, Ibraheem; Moosa, Mahdi Muhammad; Raju, Muralikrishna; Potoyan, Davit A.; Banerjee, Priya R.

doi:10.1101/2020.01.10.902353

Cited by 27 publications

(35 citation statements)

References 54 publications

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“…4, we show how Csat changes with increasing RNA concentration, At low RNA concentrations, there is an initial decrease in the Csat values (by as much as a factor of two) highlighting the LAF-1 RGG's enhanced propensity to phase separate in the presence of RNA. Similar LLPS behavior has also been observed previously in many other cases(19,57,58) which in this case is due to favorable attraction between cationic Arginine residues and anionic nucleotides.…”

supporting

confidence: 88%

“…6B). This is reminiscent of other examples where sub compartmentalization has been observed (62)(63)(64), including ones that show similarly structured organization of different components in a mixture to create sub compartments within a condensate (57,58). We then ask the question about the driving forces of these two distinct condensate architectures.…”

Section: Effect Of Protein Sequence Charge Patterning On Rna Partitiomentioning

confidence: 90%

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Sequence dependent co-phase separation of RNA-protein mixtures elucidated using molecular simulations

Regy

Dignon

Zheng

et al. 2020

Preprint

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ABSTRACTRibonucleoprotein (RNP) granules are membraneless organelles (MLOs) which majorly consist of RNA and RNA-binding proteins and are formed via liquid-liquid phase separation (LLPS). Experimental studies investigating the drivers of LLPS have shown that intrinsically disordered proteins (IDPs) and nucleic acids like RNA play a key role in modulating protein phase separation. There is currently a dearth of modelling techniques which allow one to delve deeper into how RNA plays its role as a modulator/promoter of LLPS in cells using computational methods. Here we present a coarse-grained RNA model developed to fill this gap, which together with our recently developed HPS model for protein LLPS, allows us to capture the factors driving RNA-protein co-phase separation. We explore the capabilities of the modelling framework with the LAF-1 RGG/RNA system which has been well studied in experiments and also with the HPS model previously. Further taking advantage of the fact that the HPS model maintains sequence specificity we explore the role of charge patterning on controlling RNA incorporation into condensates. With increased charge patterning we observe formation of structured or patterned condensates which suggests the possible roles of RNA in not only shifting the phase boundaries but also introducing microscopic organization in MLOs.

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supporting

confidence: 88%

Section: Effect Of Protein Sequence Charge Patterning On Rna Partitiomentioning

confidence: 90%

Sequence dependent co-phase separation of RNA-protein mixtures elucidated using molecular simulations

Regy

Dignon

Zheng

et al. 2020

Preprint

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“…Instead, driver chains and regulator chains demix to form two distinct dense phases: a driver-rich slab at the center, bordered by two regulator-rich slabs on the two sides (Figure 5b). This type of multiphase coexistence has been reported in many experimental studies 1, 7, 9-10 and in some recent computational studies, 10, 30-31 and may underlie the organization of many membraneless organelles. 1,4-6, 8 It is interesting that our highly simplified model systems recapitulate this complex phenomenon, affording us an opportunity to elucidate its general physical basis.…”

Section: Resultssupporting

confidence: 65%

Macromolecular Regulators Have Matching Effects on the Phase Equilibrium and Interfacial Tension of Biomolecular Condensates

Mazarakos

Zhou

2021

Preprint

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The interfacial tension of phase-separated biomolecular condensates affects their fusion and multiphase organization, and yet how this important property depends on the composition and interactions of the constituent macromolecules is poorly understood. Here we use molecular dynamics simulations to determine the interfacial tension and phase equilibrium of model condensate-forming systems. The model systems consist of binary mixtures of Lennard-Jones particles or chains of such particles. We refer to the two components as drivers and regulators; the former has stronger self-interactions and hence a higher critical temperature (T_c) for phase separation. In previous work, we have shown that, depending on the relative strengths of driver-regulator interactions and driver-driver interactions, regulators can either promote or suppress phase separation (i.e., increase or decrease T_c). Here we find that the effects of regulators on T_c quantitatively match the effects on interfacial tension (γ). This important finding means that, when a condensate-forming system experiences a change in macromolecular composition or a change in intermolecular interactions (e.g., by mutation or posttranslational modification, or by variation in solvent conditions such as temperature, pH, or salt), the resulting change in T_c can be used to predict the change in γ and vice versa. We also report initial results showing that disparity in intermolecular interactions drives multiphase coexistence. These findings provide much needed guidance for understanding how biomolecular condensates mediate cellular functions.

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“…However, as noted in recent work (35,53), this is only true if homotypic interactions among scaffold molecules are the primary drivers of phase separation. If condensates form via a combination of homotypic and heterotypic interactions (35,53,54), then the network of these interactions (12,20) and hence a combination of scaffold concentrations will determine the location of the phase boundary and the slopes of tie lines. In this scenario, one would have to measure the effects of ligands on the location of the phase boundary, governed jointly by the concentrations of all scaffold molecules that drive phase separation.…”

Section: Discussionmentioning

confidence: 99%

Ligand Effects on Phase Separation of Multivalent Macromolecules

Ruff

Dar

Pappu

2020

Preprint

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Biomolecular condensates are thought to form via phase transitions of multivalent macromolecules. Components of condensates have been classified as scaffolds and clients. In this classification, scaffolds drive condensate formation whereas clients partition into condensates. However, non-scaffold molecules can be ligands that modulate the phase behavior of scaffolds via preferential binding across phase boundaries. Here, we present computational results that explain how preferential binding of ligands to scaffold molecules in different phases can impact phase separation and the compositions of dense phases. We show that phase separation is destabilized by monovalent ligands. In contrast, multivalent ligands, depending on their mode of binding, can stabilize phase separation by serving as crosslinkers that network scaffold molecules. We also find that concentrations of scaffolds within dense phases are generally diluted by ligands. This arises because ligands destabilize condensates by preferentially binding to scaffolds in the dilute phase or because ligands have to be accommodated within dense phases when they bind preferentially to scaffolds in the dense phase. Importantly, we show that partition coefficients, which are routinely used for compositional profiling of condensates, say nothing about the regulatory impact of ligands on the phase behavior of scaffolds. Therefore, instead of measuring partition coefficients it becomes imperative to measure how ligands impact threshold concentrations of scaffolds. These measurements, performed as a function of ligand concentration, will help with understanding the regulation of condensates and enable the design of molecules that impact condensate formation or dissolution.

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Phase Transition of RNA-protein Complexes into Ordered Hollow Condensates

Cited by 27 publications

References 54 publications

Sequence dependent co-phase separation of RNA-protein mixtures elucidated using molecular simulations

Sequence dependent co-phase separation of RNA-protein mixtures elucidated using molecular simulations

Macromolecular Regulators Have Matching Effects on the Phase Equilibrium and Interfacial Tension of Biomolecular Condensates

Ligand Effects on Phase Separation of Multivalent Macromolecules

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