Programmable synthetic biomolecular condensates for cellular control

Dai, Yifan; Farag, Mina; Lee, Dong Hoon; Zeng, Xiangze; Kim, Kyeri; Son, Hye-In; X, Guo; Su, Jonathan; Peterson, Nikhil; Mohammed, Javid P.; Ney, Max; Shapiro, Daniel Mark; Pappu, Rohit V.; Joh, Daniel Y.; Li, You

doi:10.1038/s41589-022-01252-8

Cited by 61 publications

(69 citation statements)

References 53 publications

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“…How this plays out for condensates formed by mixtures of PLCDs with compositionally distinct preferences will need further investigation. Importantly, being able to compute moduli from simulations of the network structures of condensates 13 will allow us to design PLCD sequences with bespoke material properties 48 . This will also enable direct interrogations of how material properties affect condensate functions in vitro and in vivo.…”

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confidence: 99%

Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates

Alshareedah

Borcherds

Cohen

et al. 2023

Preprint

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We demonstrate that nascent versus aged condensates formed by prion-like low complexity domains (PLCDs) are distinct types of viscoelastic materials. Nascent PLCD condensates are terminally viscous Maxwell fluids whose viscoelastic moduli are governed by the strengths of aromatic stickers. Upon physical aging, PLCD condensates transition, on sequence-specific timescales, from fluids to non-fibrillar, elastic Kelvin-Voigt solids. Accordingly, fluid-like condensates of PLCDs are metastable, whereas elastic solids are the stable material states. Fluid-to-solid transitions are accelerated by mutations to spacers that weaken metastable fluids with respect to stable solids. Evolutionarily selected PLCD sequence features that enhance the metastabilities of fluid-like condensates are likely to render the barriers for conversion from fluids to solids to be insurmountable on timescales that are relevant to cellular processes.

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confidence: 99%

Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates

Alshareedah

Borcherds

Cohen

et al. 2023

Preprint

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“…If the enzyme is fused with a phase-separable domain capable of phase-separating at a concentration below the binding affinity of the enzyme and the substrate, the formation of a condensate with a higher concentration of enzyme in the dense phase (relative to its total concentration in the cell) will produce the enzymatic product in an earlier time point within a cell cycle than a cell containing the same amount of the enzyme but without a phase-separation domain 38 . This scenario suggests that regulating the saturation concentration of condensates can manipulate ‘when’ the designed cellular functions happen within a cell cycle 90 .…”

Section: Discussionmentioning

confidence: 99%

“…6d ). For example, if that sequestered molecule is a plasmid, then the spatial condensation would result in asymmetric plasmid partitioning, which could regulate population-level cellular behaviours 90 , 144 . The same rationale can be applied to regulate molecules that are crucial to cellular identity or cell fate upon cell division.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence suggests that the material properties of condensates are relevant to their function 2 , 55 , 89 , 90 , although much remains to be determined experimentally about their precise correlation. Experimentally, the material properties of condensates are commonly characterized by microrheology, fluorescence recovery after photobleaching (FRAP), and the partitioning of molecules of different sizes within condensates 91 .…”

Section: Condensate Properties and Functionmentioning

confidence: 99%

“…This study suggests that programming the C sat of condensates can be a powerful strategy to regulate the functional efficiency of the condensates in cells. Using the same principle to acceleration reaction, a synthetic condensate was designed to amplify transcription 90 . A synIDP–DNA-binding-protein fusion and a synIDP–transcription factor fusion collaboratively contribute to phase separation and recruit a target plasmid and RNA polymerase into the synthetic condensates formed in Escherichia coli , achieving transcription amplification.…”

Section: Synthetic Biomolecular Condensatesmentioning

confidence: 99%

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Engineering synthetic biomolecular condensates

Dai

Joh

2023

Nat Rev Bioeng

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The concept of phase-separation-mediated formation of biomolecular condensates provides a new framework to understand cellular organization and cooperativity-dependent cellular functions. With growing understanding of how biological systems drive phase separation and how cellular functions are encoded by biomolecular condensates, opportunities have emerged for cellular control through engineering of synthetic biomolecular condensates. In this Review, we discuss how to construct synthetic biomolecular condensates and how they can regulate cellular functions. We first describe the fundamental principles by which biomolecular components can drive phase separation. Next, we discuss the relationship between the properties of condensates and their cellular functions, which informs the design of components to create programmable synthetic condensates. Finally, we describe recent applications of synthetic biomolecular condensates for cellular control and discuss some of the design considerations and prospective applications.

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Materials Inspired by Living Functions

Kostiainen,

Priimagi,

Timonen

et al. 2024

Adv Funct Materials

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Engineering or mimicking living materials found in nature has the potential to transform the use of materials. Unlike classic synthetic materials which are typically optimized for static properties, economics, and recently also for sustainability, materials of life are dynamic, feedback‐controlled, evolving, and adaptive. Although synthetic materials do not typically exhibit such complicated functionalities, researchers are increasingly challenging this viewpoint and expanding material concepts toward dynamic systems inspired by selected life‐like functions. Herein, it is suggested that such materials can be approached from two perspectives: through engineering of biological organisms and their functions to provide the basis for new materials, or by producing synthetic materials with selected rudimentary life‐inspired functions. Current advances are discussed from the perspectives of (i) new material features based on built‐in memory and associative learning, (ii) emergent structures and self‐regulated designs using non‐equilibrium systems, and (iii) interfacing living and non‐living systems in the form of cellular community control and growth to open new routes for material fabrication. Strategies combining (i)–(iii) provide materials with increasingly life‐inspired responses and potential for applications in interactive autonomous devices, helping to realize next‐generation sensors, autonomous and interactive soft robots, and external control over the bioproduction of self‐organizing structural materials.

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Programmable synthetic biomolecular condensates for cellular control

Cited by 61 publications

References 53 publications

Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates

Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates

Engineering synthetic biomolecular condensates

Materials Inspired by Living Functions

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