Controlling biomolecular condensates via chemical reactions

Kirschbaum, Jan; Zwicker, David

doi:10.1098/rsif.2021.0255

Cited by 63 publications

(54 citation statements)

References 61 publications

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“…Phosphorylation by CDK-2 stabilizes the protein at these sites and promotes its activity as a scaffold to recruit additional RN proteins, which partition into nodules as clients (Banani et al, 2016;Wheeler and Hyman, 2018). Crucially, only highly phosphorylated MSH-5 is stably associated with recombination sites, so that controlling its phosphorylation regulates RN formation (Kirschbaum and Zwicker, 2021;Söding et al, 2020).…”

Section: An Active Droplet Model For the Formation Of Recombination Nodulesmentioning

confidence: 99%

Crossover patterning through kinase-regulated condensation and coarsening of recombination nodules

Zhang

Stauffer

Zwicker

et al. 2021

Preprint

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Meiotic recombination is highly regulated to ensure precise segregation of homologous chromosomes. Evidence from diverse organisms indicates that the synaptonemal complex (SC), which assembles between paired chromosomes, plays essential roles in crossover formation and patterning. Several additional "pro-crossover" proteins are also required for recombination intermediates to become crossovers. These typically form multiple foci or recombination nodules along SCs, and later accumulate at fewer, widely spaced sites. Here we report that in C. elegans CDK-2 is required to stabilize all crossover intermediates and stabilizes interactions among pro-crossover factors by phosphorylating MSH-5. Additionally, we show that the conserved RING domain proteins ZHP-3/4 diffuse along the SC and remain dynamic following their accumulation at recombination sites. Based on these and previous findings we propose a model in which recombination nodules arise through spatially restricted biomolecular condensation and then undergo a regulated coarsening process, resulting in crossover interference.

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Section: An Active Droplet Model For the Formation Of Recombination Nodulesmentioning

confidence: 99%

Crossover patterning through kinase-regulated condensation and coarsening of recombination nodules

Zhang

Stauffer

Zwicker

et al. 2021

Preprint

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“…Answering this question is directly relevant to biomolecular condensates, where hidden structures in intrinsically disordered regions might strongly affect the phase behavior of proteins [46]. Our method can also be extended to describe more complex behavior of biomolecular condensates, including response to external cues [19,47], active regulation [48][49][50], and noise buffering [51,52]. Ultimately, our predictions could be tested using engineered condensates [53] and quantitative reconstitution [33].…”

Section: Discussionmentioning

confidence: 99%

Evolved interactions stabilize many coexisting phases in multicomponent liquids

Zwicker¹,

Laan²

2022

Preprint

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Phase separation has emerged as an essential concept for the spatial organization inside biological cells. However, despite the clear relevance to virtually all physiological functions, we understand surprisingly little about what phases form in a system of many interacting components, like in cells. Here, we introduce a new numerical method based on physical relaxation dynamics to study the coexisting phases in such systems. We use our approach to optimize interactions between components, similar to how evolution might have optimized the interactions of proteins. These evolved interactions robustly lead to a defined number of phases, despite substantial uncertainties in the initial composition, while random or designed interactions perform much worse. Moreover, the optimized interactions are robust to perturbations and they allow fast adaption to new target phase counts. We thus show that genetically encoded interactions of proteins provide versatile control of phase behavior. The phases forming in our system are also a concrete example of a robust emergent property that does not rely on fine-tuning the parameters of individual constituents.

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“…due to reduced nuclear elasticity which previously has been associated with cancer, while a broadened distribution would be indicative of a "rich-get-richer" effect. However, still other factors, such as nonequilibrium activity and condensate-dependent reaction rates 46 have been described as potential regulators of condensate size. For example, nucleoli are commonly observed to exhibit an unexpected power-law distribution in size, which likely results from not only coalescence dynamics, but also from the strong influence of regulated steady-state production of ribosomal RNA.…”

Section: Discussionmentioning

confidence: 99%

A rich get richer effect governs intracellular condensate size distributions

Lee

Choi

Sanders

et al. 2022

Preprint

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Phase separation of biomolecules into condensates has emerged as a ubiquitous mechanism for intracellular organization and impacts many intracellular processes, including reaction pathways through clustering of enzymes and their intermediates. Precise and rapid spatiotemporal control of reactions by condensates requires tuning of their sizes. However, the physical processes that govern the distribution of condensate sizes remain unclear. Here, we utilize a combination of synthetic and native condensates to probe the underlying physical mechanisms determining condensate size. We find that both native nuclear speckles and FUS condensates formed with the synthetic Corelet system obey an exponential size distribution, which can be recapitulated in Monte Carlo simulations of fast nucleation followed by coalescence. By contrast, pathological aggregation of cytoplasmic Huntingtin polyQ protein exhibits a power-law size distribution, with an exponent of -1.41±0.02. These distinct behaviors reflect the relative importance of nucleation and coalescence kinetics: introducing continuous condensate nucleation into the Monte Carlo coarsening simulations gives rise to polyQ-like power-law behavior. We demonstrate that the emergence of power-law distributions under continuous nucleation reflects a ''rich get richer'' effect, whose extent may play a general role in the determination of condensate size distributions.

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Controlling biomolecular condensates via chemical reactions

Cited by 63 publications

References 61 publications

Crossover patterning through kinase-regulated condensation and coarsening of recombination nodules

Crossover patterning through kinase-regulated condensation and coarsening of recombination nodules

Evolved interactions stabilize many coexisting phases in multicomponent liquids

A rich get richer effect governs intracellular condensate size distributions

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