Abstract
Cells are inhomogeneously crowded, possessing a wide range of intracellular liquid droplets abundantly present in the cytoplasm of eukaryotic and bacterial cells, in the mitochondrial matrix and nucleoplasm of eukaryotes, and in the chloroplast’s stroma of plant cells. These proteinaceous membrane-less organelles (PMLOs) not only represent a natural method of intracellular compartmentalization, which is crucial for successful execution of various biological functions, but also serve as important means for the processing of local information and rapid response to the fluctuations in environmental conditions. Since PMLOs, being complex macromolecular assemblages, possess many characteristic features of liquids, they represent highly dynamic (or fuzzy) protein–protein and/or protein–nucleic acid complexes. The biogenesis of PMLOs is controlled by specific intrinsically disordered proteins (IDPs) and hybrid proteins with ordered domains and intrinsically disordered protein regions (IDPRs), which, due to their highly dynamic structures and ability to facilitate multivalent interactions, serve as indispensable drivers of the biological liquid–liquid phase transitions (LLPTs) giving rise to PMLOs. In this article, the importance of the disorder-based supramolecular fuzziness for LLPTs and PMLO biogenesis is discussed.
Highlights
Data accumulated to date indicate that high levels of intrinsic disorder are found in many proteinaceous membrane-less organelles (PMLOs) resident proteins and show that the PMLO formation often relies on intrinsically disordered proteins (IDPs)/intrinsically disordered protein regions (IDPRs), indicating that PMLO biogenesis is crucially dependent on intrinsic disorder [8]
The lack of stable structure in IDPs/IDPRs, the ability of such proteins to be engaged in highly dynamic, weak, multivalent interactions combined with their capability to retain a highly mobile character after undergoing liquid–liquid phase transitions (LLPTs) define the liquid-like nature of PMLOs [5]
It is likely that the structural resilience of PMLOs and their capability to exist as stable entities in the absence of enclosing membranes combined with the free exchange of the constituents with the environment are defined by the same properties of IDPs/IDPRs [5]
Summary
It is recognized that the cellular interior represents a highly crowded space, where various biological macromolecules (such as nucleic acids, polysaccharides, proteins, and ribonucleoproteins) occupy 5–40% of the cellular volume, and where the total concentration of these biological macromolecules can be as high as 80–400 mg/mL [1,2], with the total intracellular concentration of protein being expected to be up to 300 mg/mL, while the RNA levels can range from 20–100 mg/mL [3]. Using a combination of various in vivo and in vitro approaches with computational modeling, it was recently shown that one of the most studied PMLOs, the nucleolus, possesses layered droplet organization containing internal sub-compartments [60] These sub-compartments were shown to represent distinct, coexisting, non-coalescing liquid phases formed by LLPTs of specific nucleolar proteins, suggesting that biological phase separation can generate multilayered liquids [60]. Because of this environmental sensitivity and receptivity as well as the capability to undergo fast, highly controllable, environment-modulated transitions, IDPs/IDPRs play crucial roles in the regulation of LLPTs and PMLOs [5]
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