Biomolecular condensates present in cells can fundamentally affect the aggregation of amyloidogenic proteins and play a role in the regulation of this process. While liquid-liquid phase separation of amyloidogenic proteins by themselves can act as an alternative nucleation pathway, interaction of partly disordered aggregation-prone proteins with pre-existing condensates that act as localization centers could be a far more general mechanism of altering their aggregation behavior. Here, we show that so-called host biomolecular condensates can both accelerate and slow down amyloid formation. We study the amyloidogenic protein α-synuclein and two truncated α-synuclein variants in the presence of three types of condensates composed of non-aggregating peptides, RNA or ATP. Our results demonstrate that condensates can dramatically speed up amyloid formation when proteins localize to their interface. However, condensates can also significantly suppress aggregation by sequestering and stabilizing amyloidogenic proteins, thereby providing living cells with a possible protection mechanism against amyloid formation.

Biomolecular condensates can both accelerate and suppress aggregation of α-synuclein

Biomolecular condensates present in cells can fundamentally affect the aggregation of amyloidogenic proteins and play a role in the regulation of this process. While liquid-liquid phase separation of amyloidogenic proteins by themselves can act as an alternative nucleation pathway, interaction of partly disordered aggregation-prone proteins with preexisting condensates that act as localization centers could be a far more general mechanism of altering their aggregation behavior. Here, we show that so-called host biomolecular condensates can both accelerate and slow down amyloid formation. We study the amyloidogenic protein α-synuclein and two truncated α-synuclein variants in the presence of three types of condensates composed of nonaggregating peptides, RNA, or ATP. Our results demonstrate that condensates can markedly speed up amyloid formation when proteins localize to their interface. However, condensates can also significantly suppress aggregation by sequestering and stabilizing amyloidogenic proteins, thereby providing living cells with a possible protection mechanism against amyloid formation. 

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/pdf/growth-replication-and-division-enable-evolution-of-2tdhdt81.pdf

Growth, replication and division enable evolution of coacervate protocells

Cells compartmentalize their components in liquid-like condensates, which can be reconstituted in vitro. Although these condensates interact with membrane-bound organelles, the potential of membrane remodeling and the underlying mechanisms are not well understood. Here, we demonstrate that interactions between protein condensates (including hollow ones) and membranes can lead to remarkable morphological transformations and describe these with theory. Modulation of solution salinity or membrane composition drives the condensate-membrane system through two wetting transitions, from dewetting, through a broad regime of partial wetting, to complete wetting. A new phenomenon, namely fingering or ruffling of the condensate-membrane interface is observed when sufficient membrane area is available, producing intricately curved structures. The observed morphologies are governed by the interplay of adhesion, membrane elasticity, and interfacial tension. Our results highlight the relevance of wetting in cell biology, and pave the way for the design of synthetic membrane-droplet based biomaterials and compartments with tunable properties.

/pdf/wetting-and-complex-remodeling-of-membranes-by-biomolecular-19wwa4aw.pdf

Wetting and complex remodeling of membranes by biomolecular condensates

Liquid-liquid phase separation (LLPS) underlies the formation of intracellular membraneless compartments in biology and may have played a role in the formation of protocells that concentrate key chemicals during the origins of life. While LLPS of simple systems, such as oil and water, is well understood, many aspects of LLPS in complex, out-of-equilibrium molecular systems remain elusive. Here, the author discusses open questions and recent insights related to the formation, function and fate of such condensates both in cell biology and protocell research. Liquid-liquid phase separation (LLPS) underlies the formation of intracellular membraneless compartments in biology and may have played a role in the formation of protocells that concentrate key chemicals during the origins of life. While LLPS of simple systems, such as oil and water, is well understood, many aspects of LLPS in complex, out-of-equilibrium molecular systems remain elusive. Here, the author discusses open questions and recent insights related to the formation, function and fate of such condensates both in cell biology and protocell research. 

https://www.nature.com/articles/s42004-023-00823-7.pdf

Open questions on liquid–liquid phase separation

Recent studies have shown that the interactions between condensates and biological membranes are of functional importance. Here, we study how the interaction between complex coacervates and liposomes as model systems can lead to wetting, membrane deformation, and endocytosis. Depending on the interaction strength between coacervates and liposomes, the wetting behavior ranged from nonwetting to engulfment (endocytosis) and complete wetting. Endocytosis of coacervates was found to be a general phenomenon: coacervates made from a wide range of components could be taken up by liposomes. A simple theory taking into account surface energies and coacervate sizes can explain the observed morphologies. Our findings can help to better understand condensate–membrane interactions in cellular systems and provide new avenues for intracellular delivery using coacervates.

/pdf/endocytosis-of-coacervates-into-liposomes-1d80ka02.pdf

Endocytosis of Coacervates into Liposomes

Biomolecular condensates are a promising platform for synthetic cell formation and constitute a potential missing link between the chemical and cellular stage of the origins of life. However, it has proven challenging to integrate complex reaction networks into biomolecular condensates, such as a cell-free in vitro transcription-translation (IVTT) system. Integrating IVTT into biomolecular condensates successfully is one precondition for condensation-based synthetic cell formation. Moreover, it would provide a proof of concept that biomolecular condensates are in principle compatible with the central dogma, one of the hallmarks of cellular life. Here, we have systemically investigated the compatibility of eight different (bio)molecular condensates with IVTT incorporation. Of these eight candidates, we have found that a green fluorescent protein-labeled, intrinsically disordered cationic protein (GFP-K72) and single-stranded DNA (ssDNA) can form biomolecular condensates that are compatible with up to μM fluorescent protein expression. This shows that biomolecular condensates can indeed integrate complex reaction networks, confirming their use as synthetic cell platforms and hinting at a possible role in the origin of life.

https://pubs.acs.org/doi/pdf/10.1021/acssynbio.3c00069

Ludo Schoenmakers

Papers

Endocytosis of Coacervates into Liposomes

In Vitro Transcription-Translation in an Artificial Biomolecular Condensate.