Intrinsic factors behind long COVID: IV. Hypothetical roles of the SARS‐CoV‐2 nucleocapsid protein and its liquid–liquid phase separation

Journal of Cellular Biochemistry, Journal Year: 2024, Volume and Issue: 125(3)

Published: Feb. 13, 2024

Abstract When the SARS‐CoV‐2 virus infects humans, it leads to a condition called COVID‐19 that has wide spectrum of clinical manifestations, from no symptoms acute respiratory distress syndrome. The initiates damage by attaching ACE‐2 protein on surface endothelial cells line blood vessels and using these as hosts for replication. Reactive oxygen species levels are increased during viral replication, which oxidative stress. About three‐fifths (~60%) people who get infected with eradicate their body after 28 days recover normal activity. However, large fraction (~40%) suffer various (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, tachycardia) beyond 12 weeks diagnosed syndrome long COVID. Long‐term studies in group contracted have been contrasted noninfected matched people. A subset can be distinguished set cytokine markers persistent, low‐grade inflammation often self‐report two or more bothersome symptoms. No medication alleviate efficiently. Coronavirus nucleocapsid proteins investigated extensively potential drug targets due key roles among is ability bind respective genomic RNAs incorporation into emerging virions. This review highlights basic its undergo liquid–liquid phase separation. We hypothesize this separation may contribute hypothesis unlocks new investigation angles could potentially open novel avenues better understanding COVID treating condition.

Language: Английский

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Adenosine Triphosphate: The Primordial Molecule That Controls Protein Homeostasis and Shapes the Genome–Proteome Interface

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 500 - 500

Published: April 19, 2024

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid-liquid phase separation (LLPS) represents common principle formation of membrane-less organelles (MLOs) composed proteins rich in intrinsically disordered regions (IDRs) acids. Currently, IDRs are well recognized facilitate LLPS through dynamic multivalent interactions, precise mechanisms by which ATP affect still remain elusive. This review summarizes recent NMR results on human FUS, TDP-43, viral nucleocapsid (N) protein SARS-CoV-2, modulated acids, revealing following: (1) binds folded domains overlapping with nucleic-acid-binding interfaces; (2) interplay biphasically modulate competitively binding pockets Arg/Lys within IDRs; (3) energy-independently induces folding highest efficiency known so far. As likely emerged prebiotic monomeric world, a pivotal mechanism concentrate compartmentalize rare molecules forming primordial cells, appears control homeostasis shape genome-proteome interfaces throughout evolutionary trajectory, from origins modern cells.

Language: Английский

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Chandipura Virus Forms Cytoplasmic Inclusion Bodies through Phase Separation and Proviral Association of Cellular Protein Kinase R and Stress Granule Protein TIA-1

Viruses, Journal Year: 2024, Volume and Issue: 16(7), P. 1027 - 1027

Published: June 26, 2024

Negative-strand RNA viruses form cytoplasmic inclusion bodies (IBs) representing virus replication foci through phase separation or biomolecular condensation of viral and cellular proteins, as a hallmark their infection. Alternatively, mammalian cells stalled mRNA containing antiviral stress granules (SGs), consequence phosphorylation eukaryotic initiation factor 2α (eIF2α) several RNA-binding proteins including TIA-1. Whether how Chandipura (CHPV), an emerging human pathogen causing influenza-like illness, coma death, forms IBs evades SGs remain unknown. By confocal imaging on CHPV-infected Vero-E6 cells, we found that CHPV infection does not induce formation distinct canonical SGs. Instead, condense co-localize together with SG to heterogeneous IBs, which ensued independent the activation eIF2α kinase, protein kinase R (PKR). Interestingly, siRNA-mediated depletion PKR TIA-1 significantly decreased transcription virion production. Moreover, also caused recruitment IBs. Compared SGs, exhibited significant rapidity in disassembly dynamics. Altogether, our study demonstrating co-optimizes revealing unprecedented proviral role TIA-1/PKR may have implications understanding mechanisms regulating CHPV-IB designing therapeutics. Importance: is tropical reported cause acute illness encephalitis children very high mortality rate ~70%. Lack vaccines effective therapy against makes it potent for epidemic parts globe. Given these forewarnings, paramount importance biology must be understood comprehensively. Targeting host factors offers advantages over targeting components due generally higher mutation genome. In this study, aimed at forming replication. Our helps understand participation could help develop therapeutics virus.

Language: Английский

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Viral amyloids: New opportunities for antiviral therapeutic strategies

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 83, P. 102706 - 102706

Published: Sept. 30, 2023

Language: Английский

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Implications of intrinsic disorder and functional proteomics in the merkel cell polyomavirus life cycle

Journal of Cellular Biochemistry, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 9, 2023

Infection with merkel cell polyomavirus (MCPyV) is implicated in the development of carcinoma (MCC), a rare but aggressive skin cancer. MCC has mortality rate near 50%, and incidence been rapidly increasing recent decades, making improved treatment strategies critical to addressing its growing social burden. The parallel necessity for novel research better understand MCPyV pathogenesis prompted numerous studies years, yet role intrinsic disorder proteins remains unexplored. This study carries out computational characterization within proteome suggests mechanisms that may contribute oncogenicity virus invade hijack host immune systems. Our analysis finds significant levels are present LT, ALTO, 57kT, VP1, regions sT also contain large, disordered regions. investigation further shows correlation propensity outputs functional predictors eukaryotic linear motifs (ELMs), molecular recognition features (MoRFs), liquid-liquid phase separation (LLPS). findings indicate use condensation alter viral function accentuate or provide basis oncogenic activities. It intended this will inform future experimental validation efforts around capacity protein-protein interactions. Furthermore, we hope other investigators on potential life cycle toward ultimately progressing therapeutic agents.

Language: Английский

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PSPire: a machine learning predictor for high-performance screening of phase-separating proteins without intrinsically disordered regions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 24, 2023

Abstract The burgeoning comprehension of protein phase separation (PS) has ushered in a wealth bioinformatics tools for the prediction phase-separating proteins (PSPs). These often skew towards PSPs with high content intrinsically disordered regions (IDRs), thus frequently undervaluing potential without IDRs. Nonetheless, PS is not only steered by IDRs but also structured modular domains and interactions that aren’t necessarily reflected amino acid sequences. In this work, we introduce PSPire, unique machine learning predictor designed to incorporate both residue-level structure-level features precise PSPs. Compared current PSP predictors, PSPire shows notable improvement identifying IDRs, which underscores crucial role non-IDR, structure-based characteristics multivalent throughout process. Additionally, our biological validation experiments substantiate predictive capacity 6 out 8 chosen candidate confirmed form condensates within cells. This highlights considerable models accurate comprehensive understanding PS.

Language: Английский

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Targeting phase separated protein states for drug discovery

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 255 - 273

Published: Nov. 22, 2024

Language: Английский

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Various levels of phase transitions in the protein universe and around

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 213 - 254

Published: Nov. 22, 2024

Language: Английский

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Per Aspera ad Chaos: Vladimir Uversky’s Odyssey through the Strange World of Intrinsically Disordered Proteins

Biomolecules, Journal Year: 2023, Volume and Issue: 13(6), P. 1015 - 1015

Published: June 19, 2023

Until the late 1990s, we believed that protein function required a unique, well-defined 3D structure encrypted in amino acid sequence [...].

Language: Английский

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