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It’s a Kind of Magic: Biological Liquid-Liquid Phase Separation, Biomolecular Condensates, and Membrane-less Organelles

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 12967

Special Issue Editor

Department of Molecular Medicine, USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC07, Tampa, FL 33612, USA
Interests: intrinsically disordered proteins; protein folding; protein misfolding; partially folded proteins; protein aggregation; protein structure; protein function; protein stability; protein biophysics; protein bioinformatics; conformational diseases; protein–ligand interactions; protein–protein interactions; liquid-liquid phase transitions
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Special Issue Information

Dear colleagues,

Currently, there is immense interest among the scientific community in intracellular liquid–liquid phase separation (LLPS) and resulting biomolecular condensates (BMCs) and membrane-less organelles (MLOs). Obviously, such BMCs and MLOs, which do not have enclosing membranes, are mysterious subjects, whose components can directly contact, and exchange with, the exterior environment and whose biogenesis and structural integrity rely exclusively on protein–protein and/or protein–nucleic acid interactions. BMCs/MLOs, are large, highly dynamic, macromolecular ensembles visible under the light microscope as spherical micron-sized droplets. They demonstrate liquid-like behavior, being able of dripping, formation of spherical structures upon fusion, and wetting. Therefore, MLOs are condensed liquid droplets formed as a result of reversible and highly controlled LLPS. MLOs are different in size, shape, and composition, and have important and diverse biological functions. Typically, MLOs are formed in response to specific cellular activities or stress. Alterations of their biogenesis might have pathological consequences, and many MLOs are associated with the pathogenesis of various diseases. This Special Issue includes research papers and reviews dedicated to the different aspects of LLPS, BMCs, and MLOs.

Dr. Vladimir N. Uversky
Guest Editor

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Published Papers (3 papers)

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Research

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15 pages, 2106 KiB  
Article
Liquid–Liquid Phase Separation in the Presence of Macromolecular Crowding and State-dependent Kinetics
by Alick-O. Vweza, Chul-Gyu Song and Kil-To Chong
Int. J. Mol. Sci. 2021, 22(13), 6675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136675 - 22 Jun 2021
Cited by 7 | Viewed by 3718
Abstract
Biomolecular condensates formed via liquid–liquid phase separation (LLPS) are increasingly being shown to play major roles in cellular self-organization dynamics in health and disease. It is well established that macromolecular crowding has a profound impact on protein interactions, particularly those that lead to [...] Read more.
Biomolecular condensates formed via liquid–liquid phase separation (LLPS) are increasingly being shown to play major roles in cellular self-organization dynamics in health and disease. It is well established that macromolecular crowding has a profound impact on protein interactions, particularly those that lead to LLPS. Although synthetic crowding agents are used during in vitro LLPS experiments, they are considerably different from the highly crowded nucleo-/cytoplasm and the effects of in vivo crowding remain poorly understood. In this work, we applied computational modeling to investigate the effects of macromolecular crowding on LLPS. To include biologically relevant LLPS dynamics, we extended the conventional Cahn–Hilliard model for phase separation by coupling it to experimentally derived macromolecular crowding dynamics and state-dependent reaction kinetics. Through extensive field-theoretic computer simulations, we show that the inclusion of macromolecular crowding results in late-stage coarsening and the stabilization of relatively smaller condensates. At a high crowding concentration, there is an accelerated growth and late-stage arrest of droplet formation, effectively resulting in anomalous labyrinthine morphologies akin to protein gelation observed in experiments. These results not only elucidate the crowder effects observed in experiments, but also highlight the importance of including state-dependent kinetics in LLPS models, and may help in designing further experiments to probe the intricate roles played by LLPS in self-organization dynamics of cells. Full article
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24 pages, 15103 KiB  
Article
Integration of Data from Liquid–Liquid Phase Separation Databases Highlights Concentration and Dosage Sensitivity of LLPS Drivers
by Nazanin Farahi, Tamas Lazar, Shoshana J. Wodak, Peter Tompa and Rita Pancsa
Int. J. Mol. Sci. 2021, 22(6), 3017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063017 - 16 Mar 2021
Cited by 22 | Viewed by 4470
Abstract
Liquid–liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles, representing functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integrating the data on LLPS-associated proteins from dedicated databases revealed only modest agreement between them [...] Read more.
Liquid–liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles, representing functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integrating the data on LLPS-associated proteins from dedicated databases revealed only modest agreement between them and yielded a high-confidence dataset of 89 human LLPS drivers. Analysis of the supporting evidence for our dataset uncovered a systematic and potentially concerning difference between protein concentrations used in a good fraction of the in vitro LLPS experiments, a key parameter that governs the phase behavior, and the proteomics-derived cellular abundance levels of the corresponding proteins. Closer scrutiny of the underlying experimental data enabled us to offer a sound rationale for this systematic difference, which draws on our current understanding of the cellular organization of the proteome and the LLPS process. In support of this rationale, we find that genes coding for our human LLPS drivers tend to be dosage-sensitive, suggesting that their cellular availability is tightly regulated to preserve their functional role in direct or indirect relation to condensate formation. Our analysis offers guideposts for increasing agreement between in vitro and in vivo studies, probing the roles of proteins in LLPS. Full article
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Review

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24 pages, 3552 KiB  
Review
Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder
by Rambon Shamilov, Victoria L. Robinson and Brian J. Aneskievich
Int. J. Mol. Sci. 2021, 22(15), 7912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157912 - 24 Jul 2021
Cited by 6 | Viewed by 3392
Abstract
Epidermal keratinocyte proteins include many with an eccentric amino acid content (compositional bias), atypical ultrastructural fate (built-in protease sensitivity), or assembly visible at the light microscope level (cytoplasmic granules). However, when considered through the looking glass of intrinsic disorder (ID), these apparent oddities [...] Read more.
Epidermal keratinocyte proteins include many with an eccentric amino acid content (compositional bias), atypical ultrastructural fate (built-in protease sensitivity), or assembly visible at the light microscope level (cytoplasmic granules). However, when considered through the looking glass of intrinsic disorder (ID), these apparent oddities seem quite expected. Keratinocyte proteins with highly repetitive motifs are of low complexity but high adaptation, providing polymers (e.g., profilaggrin) for proteolysis into bioactive derivatives, or monomers (e.g., loricrin) repeatedly cross-linked to self and other proteins to shield underlying tissue. Keratohyalin granules developing from liquid–liquid phase separation (LLPS) show that unique biomolecular condensates (BMC) and proteinaceous membraneless organelles (PMLO) occur in these highly customized cells. We conducted bioinformatic and in silico assessments of representative keratinocyte differentiation-dependent proteins. This was conducted in the context of them having demonstrated potential ID with the prospect of that characteristic driving formation of distinctive keratinocyte structures. Intriguingly, while ID is characteristic of many of these proteins, it does not appear to guarantee LLPS, nor is it required for incorporation into certain keratinocyte protein condensates. Further examination of keratinocyte-specific proteins will provide variations in the theme of PMLO, possibly recognizing new BMC for advancements in understanding intrinsically disordered proteins as reflected by keratinocyte biology. Full article
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