Our understanding of cells has progressed rapidly in recent years, mainly because of technological advances. Modern technology now allows us to observe molecular processes in living cells with high ...spatial and temporal resolution. At the same time, we are beginning to compile the molecular parts list of cells. However, how all these parts work together to yield complex cellular behavior is still unclear. In addition, the established paradigm of molecular biology, which sees proteins as well-folded enzymes that undergo specific lock-and-key type interactions, is increasingly being challenged. In fact, it is now becoming clear that many proteins do not fold into three-dimensional structures and additionally show highly promiscuous binding behavior. Furthermore, proteins function in collectives and form condensed phases with different material properties, such as liquids, gels, glasses or filaments. Here, I examine emerging evidence that the formation of macromolecular condensates is a fundamental principle in cell biology. I further discuss how different condensed states of living matter regulate cellular functions and decision-making and ensure adaptive behavior and survival in times of cellular crisis.
We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often ...incomplete. This is a problem because it limits our ability to develop effective disease treatments. To overcome this limitation, we need new concepts to describe and comprehend the complex mechanisms underlying human diseases. Condensate formation by phase separation emerges as a new principle to explain the organization of living cells. In this review, we present emerging evidence that aberrant forms of condensates are associated with many human diseases, including cancer, neurodegeneration, and infectious diseases. We examine disease mechanisms driven by aberrant condensates, and we point out opportunities for therapeutic interventions. We conclude that phase separation provides a useful new framework to understand and fight some of the most severe human diseases.
Evidence is now mounting that liquid-liquid phase separation (LLPS) underlies the formation of membraneless compartments in cells. This realization has motivated major efforts to delineate the ...function of such biomolecular condensates in normal cells and their roles in contexts ranging from development to age-related disease. There is great interest in understanding the underlying biophysical principles and the specific properties of biological condensates with the goal of bringing insights into a wide range of biological processes and systems. The explosion of physiological and pathological contexts involving LLPS requires clear standards for their study. Here, we propose guidelines for rigorous experimental characterization of LLPS processes in vitro and in cells, discuss the caveats of common experimental approaches, and point out experimental and theoretical gaps in the field.
There is a growing awareness of the importance of liquid-liquid phase separation and the resulting biomolecular condensates in both physiological and pathological contexts. This Primer provides an overview on questions to consider when phase separation might be relevant for a biological process and guidance on experimental design, execution, and data interpretation when assessing a potential functional role for a condensate.
Highlights • Cells form membrane-less compartments to adapt to stress conditions. • Compartments form through signaling or fluctuations in physico-chemical conditions. • Membrane-less compartments ...promote recovery from stress and survival. • Compartments may act as protective devices for key cellular components.
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.
Cells under stress must adjust their physiology, metabolism, and architecture to adapt to the new conditions. Most importantly, they must down-regulate general gene expression, but at the same time ...induce synthesis of stress-protective factors, such as molecular chaperones. Here, we investigate how the process of phase separation is used by cells to ensure adaptation to stress. We summarize recent findings and propose that the solubility of important translation factors is specifically affected by changes in physical-chemical parameters such temperature or pH and modulated by intrinsically disordered prion-like domains. These stress-triggered changes in protein solubility induce phase separation into condensates that regulate the activity of the translation factors and promote cellular fitness. Prion-like domains play important roles in this process as environmentally regulated stress sensors and modifier sequences that determine protein solubility and phase behavior. We propose that protein phase separation is an evolutionary conserved feature of proteins that cells harness to regulate adaptive stress responses and ensure survival in extreme environmental conditions.
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.
Phase separation in biology Alberti, Simon
CB/Current biology,
10/2017, Letnik:
27, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Cells have to organize their complex biochemistry to regulate their metabolism and respond to changes in the environment. Traditionally, intracellular organization has been associated with ...compartments that are surrounded by lipid membranes. However, in recent years, phase transitions have emerged as a novel form of cellular organization. Phase transition is a physical process whereby a substance changes from one physical state to another. Examples are provided by the freezing of water into ice (liquid to solid) or the heating of water to generate water vapor (liquid to gas).
In this Primer, Alberti introduces the emerging topic of biological phase transitions and discusses how cells use phase transitions to regulate biological functions and activities in order to increase their fitness and chances of survival.
Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called ...membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.
Phase separation is known to play a role in a variety of cellular processes, including formation of classical membraneless organelles, signaling complexes, the cytoskeleton, and numerous other supramolecular assemblies.
The concept of phase separation provides a new framework for our understanding of the functional role of sequence degeneracy (low-complexity) and protein disorder.
Accumulating evidence points to a key role for phase transitions in human diseases associated with protein aggregation, and to the misregulation of membraneless organelles in disease.
Understanding the physical principles and molecular interactions behind protein phase separation could inspire novel biomaterials.
Proteins such as FUS phase separate to form liquid-like condensates that can harden into less dynamic structures. However, how these properties emerge from the collective interactions of many amino ...acids remains largely unknown. Here, we use extensive mutagenesis to identify a sequence-encoded molecular grammar underlying the driving forces of phase separation of proteins in the FUS family and test aspects of this grammar in cells. Phase separation is primarily governed by multivalent interactions among tyrosine residues from prion-like domains and arginine residues from RNA-binding domains, which are modulated by negatively charged residues. Glycine residues enhance the fluidity, whereas glutamine and serine residues promote hardening. We develop a model to show that the measured saturation concentrations of phase separation are inversely proportional to the product of the numbers of arginine and tyrosine residues. These results suggest it is possible to predict phase-separation properties based on amino acid sequences.
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•Phase separation of FUS requires both the N-terminal PLD and the C-terminal RBD•Tyrosine and arginine govern the saturation concentration of phase separation•Glycine maintains liquidity, whereas glutamine and serine promote hardening•An associative polymer model predicts the phase behavior of FUS family proteins
The phase-separation behavior of FUS family proteins can be predicted by the prevalence and position of specific amino acids.
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