scholarly journals Therapeutics—how to treat phase separation-associated diseases

2020 ◽  
Vol 4 (3) ◽  
pp. 331-342 ◽  
Author(s):  
Richard John Wheeler
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Conceptual Framework ◽  
Protein Function ◽  
Enzyme Inhibitors ◽  
Liquid Phase Separation ◽  
Post Translational Modification ◽  
New Paradigm ◽  
Associated Proteins ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation has drawn attention as many neurodegeneration or cancer-associated proteins are able to form liquid membraneless compartments (condensates) by liquid–liquid phase separation. Furthermore, there is rapidly growing evidence that disease-associated mutation or post-translational modification of these proteins causes aberrant location, composition or physical properties of the condensates. It is ambiguous whether aberrant condensates are always causative in disease mechanisms, however they are likely promising potential targets for therapeutics. The conceptual framework of liquid–liquid phase separation provides opportunities for novel therapeutic approaches. This review summarises how the extensive recent advances in understanding control of nucleation, growth and composition of condensates by protein post-translational modification has revealed many possibilities for intervention by conventional small molecule enzyme inhibitors. This includes the first proof-of-concept examples. However, understanding membraneless organelle formation as a physical chemistry process also highlights possible physicochemical mechanisms of intervention. There is huge demand for innovation in drug development, especially for challenging diseases of old age including neurodegeneration and cancer. The conceptual framework of liquid–liquid phase separation provides a new paradigm for thinking about modulating protein function and is very different from enzyme lock-and-key or structured binding site concepts and presents new opportunities for innovation.

scholarly journals Concentration and dosage sensitivity of proteins driving liquid-liquid phase separation

2021 ◽  
Author(s):  
Nazanin Farahi ◽  
Tamas Lazar ◽  
Shoshana J. Wodak ◽  
Peter Tompa ◽  
Rita Pancsa
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Condensate Formation ◽  
Associated Proteins ◽  
Liquid Liquid Phase Separation ◽  
In Cells ◽  
Dosage Sensitivity

AbstractLiquid-liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles (MLOs), i.e. functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integration of data on LLPS-associated proteins from dedicated databases revealed only modest overlap between them and resulted in a confident set of 89 human LLPS driver proteins. Since LLPS is highly concentration-sensitive, the underlying experiments are often criticized for applying higher-than-physiological protein concentrations. To clarify this issue, we performed a naive comparison of in vitro applied and quantitative proteomics-derived protein concentrations and discuss a number of considerations that rationalize the choice of apparently high in vitro concentrations in most LLPS studies. The validity of in vitro LLPS experiments is further supported by in vivo phase-separation experiments and by the observation that the corresponding genes show a strong propensity for dosage sensitivity. This observation implies that the availability of the respective proteins is tightly regulated in cells to avoid erroneous condensate formation. In all, we propose that although local protein concentrations are practically impossible to determine in cells, proteomics-derived cellular concentrations should rather be considered as lower limits of protein concentrations, than strict upper bounds, to be respected by in vitro experiments.

scholarly journals Quantifying liquid-liquid phase separation property of chromatin under physiological conditions using Hi-MS and Hi-C

2020 ◽  
Author(s):  
Minglei Shi ◽  
Kaiqiang You ◽  
Chao Hou ◽  
Taoyu Chen ◽  
Zhengyu Liang ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Quantitative Measurement ◽  
Biological Process ◽  
Global Analysis ◽  
Chromatin Organization ◽  
Liquid Phase Separation ◽  
Protein Functions ◽  
Associated Proteins ◽  
Liquid Liquid Phase Separation

AbstractBackgroundLiquid–liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent.ResultsHere, by combing chromatin associated protein pull-down, quantitative proteomics and 1,6-hexanediol treatment, we developed Hi-MS and defined anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantitative measurement of LLPS property of chromatin-associated proteins in their endogenous state and physiological abundance. The AICAP values were verified by previously reported experiments and were reproducible across different MS platforms. Moreover, the AICAP values were highly correlate with protein functions. Proteins act in active/regulatory biological process often exhibit low AICAP values, while proteins act in structural and repressed biological process often exhibit high AICAP values. We further revealed that chromatin organization changes more in compartment A than B, and the changes in chromatin organization at various levels, including compartments, TADs and loops are highly correlated to the LLPS properties of their neighbor nuclear condensates.ConclusionsOur work provided the first global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure, and demonstrate that the active/regulatory chromatin components, both protein (trans) and DNA (cis), exhibit more hydrophobicity-dependent LLPS properties than the repressed/structural chromatin components.

scholarly journals PhaSepDB: a database of liquid–liquid phase separation related proteins

2019 ◽  
Vol 48 (D1) ◽  
pp. D354-D359 ◽  
Author(s):  
Kaiqiang You ◽  
Qi Huang ◽  
Chunyu Yu ◽  
Boyan Shen ◽  
Cristoffer Sevilla ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Online Database ◽  
Sequence Features ◽  
The Past ◽  
Associated Proteins ◽  
Related Proteins ◽  
Convenient Interface ◽  
Liquid Liquid Phase Separation

Abstract It's widely appreciated that liquid–liquid phase separation (LLPS) underlies the formation of membraneless organelles, which function to concentrate proteins and nucleic acids. In the past few decades, major efforts have been devoted to identify the phase separation associated proteins and elucidate their functions. To better utilize the knowledge dispersed in published literature, we developed PhaSepDB (http://db.phasep.pro/), a manually curated database of phase separation associated proteins. Currently, PhaSepDB includes 2914 non-redundant proteins localized in different organelles curated from published literature and database. PhaSepDB provides protein summary, publication reference and sequence features of phase separation associated proteins. The sequence features which reflect the LLPS behavior are also available for other human protein candidates. The online database provides a convenient interface for the research community to easily browse, search and download phase separation associated proteins. As a centralized resource, we believe PhaSepDB will facilitate the future study of phase separation.

scholarly journals Liquid–Liquid Phase Separation: Undergraduate Labs on a New Paradigm for Intracellular Organization

2020 ◽  
Vol 1 (1) ◽  
pp. 5
Author(s):  
Caroline P. Riedstra ◽  
Ryan McGorty
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Aqueous System ◽  
Liquid Phase Separation ◽  
New Paradigm ◽  
Interdisciplinary Field ◽  
Quantitative Image ◽  
Membrane Bound ◽  
Biophysical Techniques ◽  
Liquid Liquid Phase Separation

Recent work has shown that the intracellular environment is organized not only through membrane-bound organelles but also through fluid droplets that emerge through liquid–liquid phase separation (LLPS). Intracellular LLPS has attracted recent attention because these fluid droplets, termed biomolecular condensates or membraneless organelles, seem to play important roles in cells' responses to stress, gene regulation, and pathologies. Our understanding of intracellular LLPS has advanced through many quantitative biophysical techniques. Here, we describe a set of undergraduate lab activities that highlight these biophysical techniques. We use various optical microscopy methods and quantitative image analysis to characterize the physical properties of a model aqueous system that exhibits liquid–liquid phase separation. These lab activities can form a multiweek module that exposes students to this exciting new and interdisciplinary field that investigates how phase transitions organize the cell interior.

scholarly journals DrLLPS: a data resource of liquid–liquid phase separation in eukaryotes

2019 ◽  
Vol 48 (D1) ◽  
pp. D288-D295 ◽  
Author(s):  
Wanshan Ning ◽  
Yaping Guo ◽  
Shaofeng Lin ◽  
Bin Mei ◽  
Yu Wu ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Model Organisms ◽  
Post Translational Modifications ◽  
Data Resource ◽  
Functional Annotations ◽  
Cancer Mutations ◽  
Associated Proteins ◽  
Liquid Liquid Phase Separation

Abstract Here, we presented an integrative database named DrLLPS (http://llps.biocuckoo.cn/) for proteins involved in liquid–liquid phase separation (LLPS), which is a ubiquitous and crucial mechanism for spatiotemporal organization of various biochemical reactions, by creating membraneless organelles (MLOs) in eukaryotic cells. From the literature, we manually collected 150 scaffold proteins that are drivers of LLPS, 987 regulators that contribute in modulating LLPS, and 8148 potential client proteins that might be dispensable for the formation of MLOs, which were then categorized into 40 biomolecular condensates. We searched potential orthologs of these known proteins, and in total DrLLPS contained 437 887 known and potential LLPS-associated proteins in 164 eukaryotes. Furthermore, we carefully annotated LLPS-associated proteins in eight model organisms, by using the knowledge integrated from 110 widely used resources that covered 16 aspects, including protein disordered regions, domain annotations, post-translational modifications (PTMs), genetic variations, cancer mutations, molecular interactions, disease-associated information, drug-target relations, physicochemical property, protein functional annotations, protein expressions/proteomics, protein 3D structures, subcellular localizations, mRNA expressions, DNA & RNA elements, and DNA methylations. We anticipate DrLLPS can serve as a helpful resource for further analysis of LLPS.

scholarly journals Emerging Roles of Liquid–Liquid Phase Separation in Cancer: From Protein Aggregation to Immune-Associated Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiahua Lu ◽  
Junjie Qian ◽  
Zhentian Xu ◽  
Shengyong Yin ◽  
Lin Zhou ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Genome Stability ◽  
Liquid Phase Separation ◽  
Cellular Stress Response ◽  
Regulation Of Transcription ◽  
Membrane Structures ◽  
New Paradigm ◽  
Nuclear Speckles ◽  
Liquid Liquid Phase Separation

Liquid–liquid Phase Separation (LLPS) of proteins and nucleic acids has emerged as a new paradigm in the study of cellular activities. It drives the formation of liquid-like condensates containing biomolecules in the absence of membrane structures in living cells. In addition, typical membrane-less condensates such as nuclear speckles, stress granules and cell signaling clusters play important roles in various cellular activities, including regulation of transcription, cellular stress response and signal transduction. Previous studies highlighted the biophysical and biochemical principles underlying the formation of these liquid condensates. The studies also showed how these principles determine the molecular properties, LLPS behavior, and composition of liquid condensates. While the basic rules driving LLPS are continuously being uncovered, their function in cellular activities is still unclear, especially within a pathological context. Therefore, the present review summarizes the recent progress made on the existing roles of LLPS in cancer, including cancer-related signaling pathways, transcription regulation and maintenance of genome stability. Additionally, the review briefly introduces the basic rules of LLPS, and cellular signaling that potentially plays a role in cancer, including pathways relevant to immune responses and autophagy.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

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