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NRMCB highlights recent progress in understanding phase separation mechanisms, the roles of biomolecular condensates in cells, and their relevance to disease. We include Reviews, a Roadmap, Comments, Journal Clubs, and a selection of recent research papers from the Nature journals.
An emerging model of gene regulation posits that DNA, RNA and proteins form condensate nuclear compartments that facilitate cooperative interactions. This Review discusses how compartmentalization can lead to non-stoichiometric molecular interactions and behaviours in transcription, co-transcriptional and post-transcriptional RNA processing, and higher-order chromatin regulation.
Biomolecular condensates, which form via liquid−liquid phase separation in a tightly regulated manner, have fundamental roles in cellular organization and physiology. Recent studies provide insight into how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates.
Biomolecular condensates are membraneless molecular assemblies formed via liquid–liquid phase separation. They have a plethora of roles, ranging from controlling biochemical reactions to regulating cell organization and cell function. This article provides a framework for the study of condensate functions across these cellular length scales, offering to bring new understanding of biological processes.
The nucleolus is a membraneless organelle involved in ribonucleoprotein assembly, including ribosome biogenesis. Recent evidence indicates that the nucleolus is a biomolecular condensate that forms via liquid–liquid phase separation (LLPS), and insights from studies within the LLPS framework are increasing our understanding of the relationship between nucleolar structure and function.
Recent studies have highlighted the contribution of RNA to cellular liquid–liquid phase separation and condensate formation. RNA features modulate the composition and biophysical properties of RNA–protein condensates, which have various cellular functions, including RNA transport and localization, supporting catalytic processes and responding to stress.
In this Comment, the authors draw attention to the role of partial order in biomolecular condensates and propose that cooperative, ordered interactions between condensate components could underlie the formation and function of these diverse macromolecular assemblies.
Rippe and Papantonis suggest that intrinsically disordered regions in transcription-relevant factors underlie the formation of both ‘transcriptional condensates’ and ‘transcription factories’.
Monika Fuxreiter discusses recent studies indicating that generic interactions that determine the biophysical properties of condensates are important for condensate function.
A 2017 paper showed that phase separation and formation of elastin in the extracellular matrix does not require protein secondary structures, but cross-linked disordered chains.
Alterations in the interactions driving phase separation of the mRNA decapping complex led to conformational rearrangements in its active site, providing a mechanism to control whether substrate mRNA is stored or decapped in condensates.
Esposito et al. show that TGF-β-induced DACT1 forms biomolecular condensates that sequester CK2 to repress Wnt signalling and modulate bone metastasis in cancer.
Branching microtubule nucleation plays a major part in cellular processes driving eukaryotic cell division. A combination of microscopy approaches and hydrodynamic theory is used to show how the condensed protein TPX2 on a microtubule reorganizes according to the Rayleigh–Plateau instability.
A mass spectrometry–based approach is used to investigate the mechanisms by which different NUP98 fusion proteins cause leukemia, revealing that the fusion proteins share common interactors and alter the composition of nuclear condensates.
The SARS-CoV-2 nucleocapsid (N) protein binds the viral RNA genome and contains two ordered domains flanked by three intrinsically-disordered regions. Here, the authors show that RNA binding induces liquid-liquid phase separation of N, which is driven by its central intrinsically-disordered region and is modulated by phosphorylation. The SARS-CoV-2 Membrane (M) protein also phase-separates with N, and three-component mixtures of N + M + RNA form mutually exclusive compartments containing N + M or N + RNA.
A theoretical model, in vitro reconstitution and in vivo experimentation show that competition between droplet surface tension and membrane sheet instability dictates the form and function of autophagosomal membranes.
Biomolecules in the cell nucleus form condensates at a rate slower than that predicted by the theory of droplet growth. Experiments on living cells attribute this anomalous coarsening behaviour to subdiffusive dynamics in the crowded nucleus.
Introducing the pyrenoid-based CO2-concentrating mechanism of green algae into crops could greatly improve photosynthesis. Here, the authors show that expression of the algal linker protein EPYC1 and a plant-algal hybrid Rubisco in Arabidopsis chloroplasts leads to formation of a phase separated algal-like proto-pyrenoid.
Xie et al. show that efficient miRNA biogenesis in Arabidopsis requires the assembly of pre-miRNA processing bodies mediated by SERRATE phase separation.
The SARS-CoV-2 viral genome is encapsulated by the nucleocapsid protein (NSARS-CoV-2) that is essential for viral replication. Here, the authors show that RNA induces liquid-liquid phase separation of NSARS-CoV-2 and how NSARS-CoV-2 phosphorylation modulates RNA-binding and phase separation and that these RNA/NSARS-CoV-2-droplets recruit and concentrate the SARS-CoV-2 RNA-dependent RNA polymerase complex in vitro, which would enable high initiation and elongation rates during viral transcription.
The structural basis of the interactions between Rubisco and its intrinsically disordered linker protein provides insight into phase separation within the algal pyrenoid, an organelle responsible for around a third of global CO2 fixation.
The self-assembly of haemoglobin-containing erythrocyte membrane fragments onto the surface of preformed coacervates has been used to make hybrid synthetic cells that can initiate nitric-oxide-induced vasodilation. These synthetic cells encapsulate enzymes that generate a flux of nitric oxide, as well as exhibiting high haemocompatibility and increased blood circulation times.
The components of active zones at neuronal synapses are well known, but the processes underlying the assembly of these structures are less so; here, a role for liquid–liquid phase separation of scaffold proteins is identified.
Using cryo-electron tomography to detect individual GABAA receptors in hippocampal synapses, we discovered a hierarchical and mesophasic organization of inhibitory postsynaptic density proteins that enables efficient synaptic transmission.
Wei et al. show that clusters of unphosphorylated RNA polymerase II seed the nucleation of phase-separated condensates of TAF15, which further recruit RNA polymerase II to amplify transcriptional activation.
A protein condensate formed by multivalent interactions between the long non-coding RNA Xist and specific RNA-binding proteins drives the compartmentalization required to perpetuate gene silencing on the inactive X chromosome.
The adaptability of the plant Arabidopsis thaliana to different temperatures is regulated by the ability of its ELF3 protein to undergo liquid–liquid phase separation, in a manner that is dependent on the protein’s prion-like domain.
Artificial intrinsically disordered proteins (A-IDPs) have now been shown to form exclusionary, intracellular droplets that can be designed using simple principles that are based on the aromatic/aliphatic ratio and molecular weight. Droplets that sequester an enzyme and modulate enzyme efficiency on the basis of the molecular weight of the A-IDPs were also engineered using A-IDPs as a minimal condensate scaffold.
The chromatin protein MeCP2 is a component of dynamic, liquid-like heterochromatin condensates, and the ability of MeCP2 to form condensates is disrupted by mutations in the MECP2 gene that occur in the neurodevelopmental disorder Rett syndrome.
A synthetic phase separation system consisting of two protein components with tunable parameters was developed to visualize and characterize phase diagrams in living cells, revealing that increasing the interaction affinity enhances phase separation and the viscosity of condensates in vivo.
The mechanism of nucleation for α-synuclein (α-Syn) aggregation and amyloid formation in Parkinson’s disease is unclear. Now, α-Syn has been shown to undergo liquid–liquid phase separation and a liquid-to-solid-like transition leading to amyloid fibril formation. This raises the possibility that liquid–liquid phase separation is a key pathogenic mechanism behind α-Syn aggregation in Parkinson’s disease.
Heterotypic multicomponent interactions are shown to dominate the liquid–liquid phase separation that enables the formation of intracellular condensates.
Following cell division, phase separation of the transmembrane adaptor LEM2 ensures that the ESCRT machinery remodels microtubules and seals the nuclear envelope.
The chaperone Hsp27 prevents FUS from undergoing liquid–liquid phase separation until stress-induced phosphorylation causes Hsp27 to partition with FUS to preserve the liquid phase against amyloid fibril formation.
Wu et al. show that TAZ can undergo phase separation and the resulting condensates locally concentrate transcriptional activators to facilitate the expression of TAZ-controlled genes.
A combination of cellular, in vitro phase separation and functional assays shows that the intrinsically disordered regions and bromodomains of the BRD4 short isoform induce formation of liquid-like condensates in cancer cell nuclei and enhance transcriptional activity.
The yeast E3 ligase Bre1 forms a core–shell condensate with the scaffold protein Lge1, implicating liquid–liquid phase separation as a mechanism in the ubiquitination of histone H2B along gene bodies.
The pre-autophagosomal structure in yeast is a liquid-like condensate of Atg proteins whose phase separation may have a critical, active role in autophagy.
Hyperosmotic stress leads to a phase separation of the proteasome, triggered by interactions between RAD23B and ubiquitylated proteins, which bring together p97 and proteasome-associated proteins into nuclear proteolytic foci.
Genome dynamics allow cells to repair DNA double-strand breaks (DSBs), which are highly toxic DNA lesions. Here the authors reveal that in S. cerevisiae, Rad52 DNA repair proteins assemble in liquid droplets that work with dynamic nuclear microtubules to relocalize lesions to the nuclear periphery for repair.
The microtubule binding protein TPX2 enhances branching microtubule nucleation though the current mechanisms are unclear. Here, the authors show that TPX2 undergoes liquid-liquid phase separation and co-condensates with tubulin to enhance TPX2-mediated microtubule nucleation.