Biomolecular condensates are membraneless intracellular assemblies that often form via liquid-liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years ...has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss 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. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.
Why do cells age? Recent advances show that the cytoplasm is organized into many membrane‐less compartments via a process known as phase separation, which ensures spatiotemporal control over ...diffusion‐limited biochemical reactions. Although phase separation is a powerful mechanism to organize biochemical reactions, it comes with the trade‐off that it is extremely sensitive to changes in physical‐chemical parameters, such as protein concentration, pH, or cellular energy levels. Here, we highlight recent findings showing that age‐related neurodegenerative diseases are linked to aberrant phase transitions in neurons. We discuss how these aberrant phase transitions could be tied to a failure to maintain physiological physical‐chemical conditions. We generalize this idea to suggest that the process of cellular aging involves a progressive loss of the organization of phase‐separated compartments in the cytoplasm.
Phase transitions are emerging as a new mechanism of intracellular organization. Here, we hypothesize that age‐related fluctuations in physical‐chemical parameters trigger aberrant phase transitions with a consequent loss of control over intracellular organization. Our concept may explain many hallmarks of aging and the increasing risk of disease with age.
Liquid-liquid phase separation in biology Hyman, Anthony A; Weber, Christoph A; Jülicher, Frank
Annual review of cell and developmental biology,
01/2014, Letnik:
30
Journal Article
Recenzirano
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Cells organize many of their biochemical reactions in non-membrane compartments. Recent evidence has shown that many of these compartments are liquids that form by phase separation from the ...cytoplasm. Here we discuss the basic physical concepts necessary to understand the consequences of liquid-like states for biological functions.
Prion-like RNA binding proteins (RBPs) such as TDP43 and FUS are largely soluble in the nucleus but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins ...soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNA critically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.
The critical importance of controlling the size and number of intracellular organelles has led to a variety of mechanisms for regulating the formation and growth of cellular structures. In this ...review, we explore a class of mechanisms for organelle growth control that rely primarily on the cytoplasm as a ‘limiting pool’ of available material. These mechanisms are based on the idea that, as organelles grow, they incorporate subunits from the cytoplasm. If this subunit pool is limited, organelle growth will lead to depletion of subunits from the cytoplasm. Free subunit concentration therefore provides a measure of the number of incorporated subunits and thus the current size of the organelle. Because organelle growth rates are typically a function of subunit concentration, cytoplasmic depletion links organelle size, free subunit concentration, and growth rates, ensuring that as the organelle grows, its rate of growth slows. Thus, a limiting cytoplasmic pool provides a powerful mechanism for size-dependent regulation of growth without recourse to active mechanisms to measure size or modulate growth rates. Variations of this general idea allow not only for size control, but also cell-size-dependent scaling of cellular structures, coordination of growth between similar structures within a cell, and the enforcement of singularity in structure formation, when only a single copy of a structure is desired. Here, we review several examples of such mechanisms in cellular processes as diverse as centriole duplication, centrosome and nuclear size control, cell polarity, and growth of flagella.
ATP as a biological hydrotrope Patel, Avinash; Malinovska, Liliana; Saha, Shambaditya ...
Science (American Association for the Advancement of Science),
05/2017, Letnik:
356, Številka:
6339
Journal Article
Recenzirano
Hydrotropes are small molecules that solubilize hydrophobic molecules in aqueous solutions. Typically, hydrotropes are amphiphilic molecules and differ from classical surfactants in that they have ...low cooperativity of aggregation and work at molar concentrations. Here, we show that adenosine triphosphate (ATP) has properties of a biological hydrotrope. It can both prevent the formation of and dissolve previously formed protein aggregates. This chemical property is manifested at physiological concentrations between 5 and 10 millimolar. Therefore, in addition to being an energy source for biological reactions, for which micromolar concentrations are sufficient, we propose that millimolar concentrations of ATP may act to keep proteins soluble. This may in part explain why ATP is maintained in such high concentrations in cells.
The organization of a cell emerges from the interactions in protein networks. The interactome is critically dependent on the strengths of interactions and the cellular abundances of the connected ...proteins, both of which span orders of magnitude. However, these aspects have not yet been analyzed globally. Here, we have generated a library of HeLa cell lines expressing 1,125 GFP-tagged proteins under near-endogenous control, which we used as input for a next-generation interaction survey. Using quantitative proteomics, we detect specific interactions, estimate interaction stoichiometries, and measure cellular abundances of interacting proteins. These three quantitative dimensions reveal that the protein network is dominated by weak, substoichiometric interactions that play a pivotal role in defining network topology. The minority of stable complexes can be identified by their unique stoichiometry signature. This study provides a rich interaction dataset connecting thousands of proteins and introduces a framework for quantitative network analysis.
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•Human interactome dataset connecting 5,400 proteins with 28,500 interactions•Three quantitative dimensions measure specificities, stoichiometries, and abundances•Stable complexes are rare but stand out by a signature of balanced stoichiometries•Weak interactions dominate the network and have critical topological properties
Weak interactions shape the cellular protein interaction network as determined from proteomic measures of cellular interaction specificities, the strength of those interactions, and the cellular copy numbers of the proteins involved.
Compartmentalization is a characterizing feature of complexity in cells, used to organize their biochemistry. Membrane-bound organelles are most widely known, but non-membrane-bound liquid organelles ...also exist. These have recently been shown to form by phase separation of specific types of proteins known as scaffolds. This forms two phases: a condensate that is enriched in scaffold protein separated by a phase boundary from the cytoplasm or nucleoplasm with a low concentration of the scaffold protein. Phase separation is well known for synthetic polymers, but also appears important in cells. Here, we review the properties of proteins important for forming these non-membrane-bound organelles, focusing on the energetically favourable interactions that drive condensation. On this basis we make qualitative predictions about how cells may control compartmentalization by condensates; the partition of specific molecules to a condensate; the control of condensation and dissolution of condensates; and the regulation of condensate nucleation. There are emerging data supporting many of these predictions, although future results may prove incorrect. It appears that many molecules may have the ability to modulate condensate formation, making condensates a potential target for future therapeutics. The emerging properties of condensates are fundamentally unlike the properties of membrane-bound organelles. They have the capacity to rapidly integrate cellular events and act as a new class of sensors for internal and external environments.
This article is part of the theme issue ‘Self-organization in cell biology’.
Beyond Oil and Water—Phase Transitions in Cells Hyman, Anthony A.; Simons, Kai
Science (American Association for the Advancement of Science),
08/2012, Letnik:
337, Številka:
6098
Journal Article
Recenzirano
The organization of cellular compartments may be driven by liquid phase separations and the collective low-affinity interactions of macromolecules.
Contemporary biology has identified many proteins ...involved in different cellular processes, but we are far from understanding how they perform the tasks that cell functions require. How do collections of proteins and other molecules come together to form compartments (
1
) containing large numbers of macromolecular machines that execute specific and complex reactions? The search for underlying principles has been reinvigorated recently in part by insights into the role of phase transitions in organizing cellular compartments.
It has been proposed that during the early steps in the origin of life, small droplets could have formed via the segregation of molecules from complex mixtures by phase separation. These droplets ...could have provided chemical reaction centres. However, whether these droplets could divide and propagate is unclear. Here we examine the behaviour of droplets in systems that are maintained away from thermodynamic equilibrium by an external supply of energy. In these systems, droplets grow by the addition of droplet material generated by chemical reactions. Surprisingly, we find that chemically driven droplet growth can lead to shape instabilities that trigger the division of droplets into two smaller daughters. Therefore, chemically active droplets can exhibit cycles of growth and division that resemble the proliferation of living cells. Dividing active droplets could serve as a model for prebiotic protocells, where chemical reactions in the droplet play the role of a prebiotic metabolism.
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