Charge Segregation in the Intrinsically Disordered Region Governs VRN1 and DNA Liquid-like Phase Separation Robustness

Wang, Yanyan; Zhou, Huabin; Sun, Xiangyu; Huang, Qiaojing; Li, Siyang; Liu, Zhongfan; Lai, Luhua

doi:10.1016/j.jmb.2021.167269

Cited by 19 publications

(8 citation statements)

References 56 publications

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“…In agreement with the preceding results, Zacco et al [25] found that longer RNA strands present weaker dissociation constants with N-RRM1-2 domains of TDP-43 (which, like PR 25 , cannot phase separate on their own at physiological conditions) than 3-fold shorter RNA strands. Moreover, it has been recently shown that length and charge segregation in the IDR domain of VRN1-like proteins has a critical impact on modulating DNA-induced VRN1 phase separation, where liquid-like, gel-like or no phase-separation behaviour can be switched depending on the IDR length and the presence of neutral vs. charged residues [133]. Another study by Maharana et al [27] showed that smaller RNAs were more potent than larger ones in solubilizing protein condensates at high RNA concentration, which in turn, indirectly supports our observations that very short RNA strands can remotely promote LLPS for proteins that heavily rely on heterotypic interactions.…”

Section: Rna Length Has Distinct Effects On the Stability Of Condensa...mentioning

confidence: 99%

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

et al. 2022

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Biomolecular condensates formed via liquid–liquid phase separation (LLPS) play a crucial role in the spatiotemporal organization of the cell material. Nucleic acids can act as critical modulators in the stability of these protein condensates. To unveil the role of RNA length in regulating the stability of RNA binding protein (RBP) condensates, we present a multiscale computational strategy that exploits the advantages of a sequence-dependent coarse-grained representation of proteins and a minimal coarse-grained model wherein proteins are described as patchy colloids. We find that for a constant nucleotide/protein ratio, the protein fused in sarcoma (FUS), which can phase separate on its own—i.e., via homotypic interactions—only exhibits a mild dependency on the RNA strand length. In contrast, the 25-repeat proline-arginine peptide (PR25), which does not undergo LLPS on its own at physiological conditions but instead exhibits complex coacervation with RNA—i.e., via heterotypic interactions—shows a strong dependence on the length of the RNA strands. Our minimal patchy particle simulations suggest that the strikingly different effect of RNA length on homotypic LLPS versus RBP–RNA complex coacervation is general. Phase separation is RNA-length dependent whenever the relative contribution of heterotypic interactions sustaining LLPS is comparable or higher than those stemming from protein homotypic interactions. Taken together, our results contribute to illuminate the intricate physicochemical mechanisms that influence the stability of RBP condensates through RNA inclusion.

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Section: Rna Length Has Distinct Effects On the Stability Of Condensa...mentioning

confidence: 99%

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

et al. 2022

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“…Our results are consistent with the experimental observation that longer RNA strands present weaker dissociation constants with N-RRM1-2 domains of TDP-43 (which, like PR 25 , cannot phase separate on their own at physiological conditions) than 3-fold shorter RNA strands [33]. It has also been shown that length and charge segregation in the IDR domain of VRN1-like proteins has a critical impact on modulating the DNA-induced VRN1 phase separation, where liquidlike, gel-like or no phase-separation behaviour can be switched depending on the IDR length and the presence of neutral vs. highly charged domains [107]. Overall, our patchy particle results presented here, highlight that the RNA length-and-concentration-dependent reentrant phase behaviour observed for both homotypic and heterotypic phase-separating proteins is a general property of soft-matter systems, like biomolecules.…”

Section: Self-avoiding Polymers Trigger Concentration-dependent Reent...mentioning

confidence: 99%

Surfactants or scaffolds? RNAs of different lengths exhibit heterogeneous distributions and play diverse roles in RNA-protein condensates

Sanchez-Burgos

Herriott

Collepardo-Guevara

et al. 2022

Preprint

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Biomolecular condensates, thought to form via liquid-liquid phase separation of intracellular mixtures, are multicomponent systems that can include diverse types of proteins and RNAs. RNA is a critical modulator of RNA-protein condensate stability, as it induces an RNA-concentration dependent reentrant phase transition-increasing stability at low RNA concentrations and decreasing it at high concentrations. Beyond concentration, RNAs inside condensates can be heterogeneous in length, sequence, and structure. Here, we use multiscale simulations to understanding how different RNA parameters interact with one another to modulate the properties of RNA-protein condensates. To do so, we perform residue/nucleotide-resolution coarse-grained Molecular Dynamics simulations of multicomponent RNA-protein condensates containing RNAs of different lengths and concentrations, and either FUS or PR25 proteins. Our simulations reveal that RNA length regulates the reentrant phase behaviour of RNA-protein condensates: increasing RNA length sensitively rises the maximum value that the critical temperature of the mixture reaches, and the maximum concentration of RNA that the condensate can incorporate before beginning to become unstable. Strikingly, RNA of different lengths are organised heterogeneously inside condensates, which allows them to enhance condensate stability via two distinct mechanisms: shorter RNA chains accumulate at the condensate's surface acting as natural biomolecular surfactants, whilst longer RNA chains concentrate inside the core to saturate their bonds and enhance the density of molecular connections in the condensate. Using a patchy particle model, we demonstrate that the combined impact of RNA length and concentration on condensate properties is dictated by the valency, binding affinity, and polymer length of the various biomolecules involved. Our results postulate that diversity on RNA parameters within condensates allows RNAs to increase condensate stability by fulfilling two different criteria: maximizing enthalpic gain and minimizing interfacial free energy; hence, RNA diversity should be considered when assessing the impact of RNA on biomolecular condensates regulation.

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Section: Introductionmentioning

confidence: 99%

“…In parallel, specific examples have accumulated of well-defined structure in sequences which would, by existing heuristics, be overwhelmingly predicted to be disordered: alpha-helices in myosin [27] and caldesmon [28], and a coiled-coil region in the mRNA export protein GLE1 [29]. Indeed, there is a long-established connection between charge patterning and helix formation [10–13,30,31]. Finally, new methods now permit more reliable and farther-reaching assessment of the disorder presumption for highly charged regions, notably high-quality structure prediction [32,33].…”

Section: Introductionmentioning

confidence: 99%

Pervasive, conserved secondary structure in highly charged protein regions

Triandafillou

Pan

Dinner

et al. 2023

Preprint

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Understanding how protein sequences confer function remains a defining challenge in molecular biology. Two approaches have yielded enormous insight yet are often pursued separately: structure-based, where sequence-encoded structures mediate function, and disorder-based, where sequences dictate physicochemical and dynamical properties which determine function in the absence of stable structure. Here we study highly charged protein regions (>40% charged residues), which are routinely presumed to be disordered. Using recent advances in structure prediction and experimental structures, we show that roughly 40% of these regions form well-structured helices. Features often used to predict disorder—high charge density, low hydrophobicity, low sequence complexity, and evolutionarily varying length—are also compatible with solvated, variable-length helices. We show that a simple composition classifier predicts the existence of structure far better than well-established heuristics based on charge and hydropathy. We show that helical structure is more prevalent than previously appreciated in highly charged regions of diverse proteomes and characterize the conservation of highly charged regions. Our results underscore the importance of integrating, rather than choosing between, structure- and disorder-based approaches.

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Charge Segregation in the Intrinsically Disordered Region Governs VRN1 and DNA Liquid-like Phase Separation Robustness

Cited by 19 publications

References 56 publications

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

Surfactants or scaffolds? RNAs of different lengths exhibit heterogeneous distributions and play diverse roles in RNA-protein condensates

Pervasive, conserved secondary structure in highly charged protein regions

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