scholarly journals How Do Flaviviruses Hijack Host Cell Functions by Phase Separation?

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1479
Author(s):  
Akatsuki Saito ◽  
Maya Shofa ◽  
Hirotaka Ode ◽  
Maho Yumiya ◽  
Junki Hirano ◽  
...  
Keyword(s):  
Phase Separation ◽  
Host Cell ◽  
Intrinsically Disordered Proteins ◽  
Current Knowledge ◽  
Antiviral Drug ◽  
Viral Proteins ◽  
Disordered Proteins ◽  
Cell Organelles ◽  
Intrinsically Disordered ◽  
Cell Functions

Viral proteins interact with different sets of host cell components throughout the viral life cycle and are known to localize to the intracellular membraneless organelles (MLOs) of the host cell, where formation/dissolution is regulated by phase separation of intrinsically disordered proteins and regions (IDPs/IDRs). Viral proteins are rich in IDRs, implying that viruses utilize IDRs to regulate phase separation of the host cell organelles and augment replication by commandeering the functions of the organelles and/or sneaking into the organelles to evade the host immune response. This review aims to integrate current knowledge of the structural properties and intracellular localizations of viral IDPs to understand viral strategies in the host cell. First, the properties of viral IDRs are reviewed and similarities and differences with those of eukaryotes are described. The higher IDR content in viruses with smaller genomes suggests that IDRs are essential characteristics of viral proteins. Then, the interactions of the IDRs of flaviviruses with the MLOs of the host cell are investigated with emphasis on the viral proteins localized in the nucleoli and stress granules. Finally, the possible roles of viral IDRs in regulation of the phase separation of organelles and future possibilities for antiviral drug development are discussed.

scholarly journals Natural and designed proteins inspired by extremotolerant organisms can form condensates and attenuate apoptosis in human cells

2021 ◽  
Author(s):  
Mike T. Veling ◽  
Dan T. Nguyen ◽  
Nicole N. Thadani ◽  
Michela E. Oster ◽  
Nathan J. Rollins ◽  
...  
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Human Cells ◽  
Disordered Proteins ◽  
Cellular Protection ◽  
Intrinsically Disordered ◽  
Apoe Protein ◽  
Condensate Formation ◽  
Associated Proteins ◽  
Induced Apoptosis

ABSTRACTMany organisms can survive extreme conditions and successfully recover to normal life. This extremotolerant behavior has been attributed in part to repetitive, amphipathic, and intrinsically disordered proteins that are upregulated in the protected state. Here, we assemble a library of approximately 300 naturally-occurring and designed extremotolerance-associated proteins to assess their ability to protect human cells from chemically-induced apoptosis. We show that proteins from tardigrades, nematodes, and the Chinese giant salamander are apoptosis protective. Notably, we identify a region of the human ApoE protein with similarity to extremotolerance-associated proteins that also protects against apoptosis. This region mirrors the phase separation behavior seen with such proteins, like the tardigrade protein CAHS2. Moreover, we identify a synthetic protein, DHR81, that shares this combination of elevated phase separation propensity and apoptosis protection. Finally, we demonstrate that driving protective proteins into the condensate state increases apoptosis protection, and highlight the ability for DHR81 condensates to sequester caspase-7. Taken together, this work draws a link between extremotolerance-associated proteins, condensate formation, and human cellular protection.

Charge pattern affects the structure and dynamics of polyampholyte condensates

2020 ◽  
Vol 22 (34) ◽  
pp. 19368-19375 ◽  
Author(s):  
Milan Kumar Hazra ◽  
Yaakov Levy
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Intrinsically Disordered Proteins ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Internal Diffusion ◽  
Intrinsically Disordered ◽  
Structure And Dynamics ◽  
Liquid Liquid Phase Separation

The charge pattern of intrinsically disordered proteins affects the dynamics and internal diffusion of their condensate formed via liquid–liquid phase separation.

scholarly journals The Dynamism of Intrinsically Disordered Proteins in Liquid-Liquid Phase Separation

2020 ◽  
Vol 118 (3) ◽  
pp. 60a
Author(s):  
Samrat Mukhopadhyay ◽  
Anupa Majumdar ◽  
Priyanka Dogra ◽  
Shiny Maity ◽  
Ashish Joshi
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Intrinsically Disordered Proteins ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Liquid Liquid Phase Separation

scholarly journals Identifying sequence perturbations to an intrinsically disordered protein that determine its phase-separation behavior

2020 ◽  
Vol 117 (21) ◽  
pp. 11421-11431 ◽  
Author(s):  
Benjamin S. Schuster ◽  
Gregory L. Dignon ◽  
Wai Shing Tang ◽  
Fleurie M. Kelley ◽  
Aishwarya Kanchi Ranganath ◽  
...  
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Sequence Features ◽  
Intrinsically Disordered ◽  
Arginine Residues

Phase separation of intrinsically disordered proteins (IDPs) commonly underlies the formation of membraneless organelles, which compartmentalize molecules intracellularly in the absence of a lipid membrane. Identifying the protein sequence features responsible for IDP phase separation is critical for understanding physiological roles and pathological consequences of biomolecular condensation, as well as for harnessing phase separation for applications in bioinspired materials design. To expand our knowledge of sequence determinants of IDP phase separation, we characterized variants of the intrinsically disordered RGG domain from LAF-1, a model protein involved in phase separation and a key component of P granules. Based on a predictive coarse-grained IDP model, we identified a region of the RGG domain that has high contact probability and is highly conserved between species; deletion of this region significantly disrupts phase separation in vitro and in vivo. We determined the effects of charge patterning on phase behavior through sequence shuffling. We designed sequences with significantly increased phase separation propensity by shuffling the wild-type sequence, which contains well-mixed charged residues, to increase charge segregation. This result indicates the natural sequence is under negative selection to moderate this mode of interaction. We measured the contributions of tyrosine and arginine residues to phase separation experimentally through mutagenesis studies and computationally through direct interrogation of different modes of interaction using all-atom simulations. Finally, we show that despite these sequence perturbations, the RGG-derived condensates remain liquid-like. Together, these studies advance our fundamental understanding of key biophysical principles and sequence features important to phase separation.

scholarly journals Assemblages: Functional units formed by cellular phase separation

2014 ◽  
Vol 206 (5) ◽  
pp. 579-588 ◽  
Author(s):  
Jeffrey A. Toretsky ◽  
Peter E. Wright
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Intrinsic Disorder ◽  
Low Complexity ◽  
Disordered Proteins ◽  
Intracellular Space ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disease States ◽  
Membrane Bound

The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions. These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term “assemblage.” Intrinsically disordered proteins (IDPs) play an important role in forming a subset of cellular assemblages by promoting phase separation. Recent work points to an involvement of assemblages in disease states, indicating that intrinsic disorder and phase transitions should be considered in the development of therapeutics.

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