Self-assembly coupled to liquid-liquid phase separation

PLoS Computational Biology, Journal Year: 2023, Volume and Issue: 19(5), P. e1010652 - e1010652

Published: May 15, 2023

Liquid condensate droplets with distinct compositions of proteins and nucleic acids are widespread in biological cells. While it is known that such droplets, or compartments, can regulate irreversible protein aggregation, their effect on reversible self-assembly remains largely unexplored. In this article, we use kinetic theory solution thermodynamics to investigate the liquid-liquid phase separation structures well-defined sizes architectures. We find that, when assembling subunits preferentially partition into liquid robustness against traps maximum achievable assembly rates be significantly increased. particular, both range conditions leading productive corresponding increase by orders magnitude. analyze rate equation predictions using simple scaling estimates identify effects as a function relevant control parameters. These results may elucidate processes underlie normal cellular functions pathogenesis, suggest strategies for designing efficient bottom-up nanomaterials applications.

Language: Английский

---

Modulation of biophysical properties of nucleocapsid protein in the mutant spectrum of SARS-CoV-2

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Feb. 6, 2024

Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage uniquely large genomic database SARS-CoV-2, we examine impact mutations across spectrum viable amino acid sequences on biophysical phenotypes highly expressed multifunctional nucleocapsid protein. We find variation in physicochemical parameters its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also observe functional constraints that similarly occur related coronaviruses. In experiments with several N-protein species carrying associated major variants, point IDRs can have nonlocal modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, liquid-liquid phase separation. Omicron variant, distant different compensatory effects shifting delicate balance interactions controlling assembly properties, include creation new protein-protein interaction interface N-terminal IDR through defining P13L mutation. A picture emerges where genetic accompanied by significant characteristics species, particular IDRs.

Language: Английский

---

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Protein Science, Journal Year: 2024, Volume and Issue: 33(4)

Published: March 27, 2024

Abstract The rationale for replacing the old binary of structure–function with trinity structure, disorder, and function has gained considerable ground in recent years. A continuum model based on expanded form existing paradigm can now subsume importance both conformational flexibility intrinsic disorder protein function. is actually critical understanding protein–protein interactions many regulatory processes, formation membrane‐less organelles, our revised notions specificity as amply illustrated by moonlighting proteins. While its amyloids prions often discussed, roles infectious diseases under extreme conditions are also becoming clear. This review an attempt to discuss how current function, specificity, evolution fit better model. integration structure a single may bring greater clarity continuing quest proteins molecular mechanisms their functionality.

Language: Английский

---

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

---

The Key to Increase Immunogenicity of Next-Generation COVID-19 Vaccines Lies in the Inclusion of the SARS-CoV-2 Nucleocapsid Protein

Journal of Immunology Research, Journal Year: 2024, Volume and Issue: 2024, P. 1 - 18

Published: May 29, 2024

Vaccination is one of the most effective prophylactic public health interventions for prevention infectious diseases such as coronavirus disease (COVID-19). Considering ongoing need new COVID-19 vaccines, it crucial to modify our approach and incorporate more conserved regions severe acute respiratory syndrome 2 (SARS-CoV-2) effectively address emerging viral variants. The nucleocapsid protein a structural SARS-CoV-2 that involved in replication immune responses. Furthermore, this offers significant advantages owing minimal accumulation mutations over time inclusion key T-cell epitopes critical immunity. A novel strategy may be suitable generation vaccines against use combination antigens, including spike proteins, elicit robust humoral potent cellular responses, along with long-lasting strategic multiple antigens aims enhance vaccine efficacy broaden protection viruses, their response from other long-lasting, can persist up 11 years post-infection. Thus, incorporation nucleocapsids (N) into design adds an important dimension vaccination efforts holds promise bolstering ability combat effectively. In review, we summarize preclinical studies evaluated antigen. This study discusses alone its or proteins SARS-CoV-2.

Language: Английский

---