Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 17039 - 17039

Published: Dec. 1, 2023

Consistent with well-established biochemical properties of coronaviruses, sialylated glycan attachments between SARS-CoV-2 spike protein (SP) and host cells are key to the virus’s pathology. SP attaches aggregates red blood (RBCs), as shown in many pre-clinical clinical studies, causing pulmonary extrapulmonary microthrombi hypoxia severe COVID-19 patients. heavily surfaces platelets (which, like RBCs, have no ACE2) endothelial (having minimal compound this vascular damage. Notably, experimentally induced RBC aggregation vivo causes same morbidities for COVID-19, including microvascular occlusion, clots, myocarditis. Key risk factors morbidity, older age, diabetes obesity, all characterized by markedly increased propensity clumping. For mammalian species, degree susceptibility correlates aggregability p = 0.033. five human betacoronaviruses, two common cold strains express an enzyme that releases attachments, while deadly SARS, MERS do not, although viral loads infections similar. These insights also explain previously puzzling efficacy certain generics against may support development future therapeutic strategies long COVID

Language: Английский

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The Magic of Proteases: From a Procoagulant and Anticoagulant Factor V to an Equitable Treatment of Its Inherited Deficiency

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6243 - 6243

Published: March 26, 2023

Proteostasis, i.e., the homeostasis of proteins, responsible for ensuring protein turnover, is regulated by proteases, which also participate in etiopathogenesis multiple conditions. The magic proteases such that, blood coagulation, one same molecule, as coagulation factor V, example, can perform both a procoagulant and an anticoagulant function result activity proteases. However, this has insidious side to it, it may prevent completion clinical value chain V deficiency. This encompasses discovery knowledge, transfer its translation practice. In case rare ultra-rare diseases like deficiency, not been completed knowledge acquisition phase dragged out over time, holding up reason related small number patients afflicted with these As result, new indications must be found make therapies cost-effective. significant research efforts have directed at developing recombinant capable resisting action inactivating factor. where bioethics health equity considerations come into equation.

Language: Английский

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Utilizing Molecular Dynamics Simulations, Machine Learning, Cryo-EM, and NMR Spectroscopy to Predict and Validate Protein Dynamics

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9725 - 9725

Published: Sept. 8, 2024

Protein dynamics play a crucial role in biological function, encompassing motions ranging from atomic vibrations to large-scale conformational changes. Recent advancements experimental techniques, computational methods, and artificial intelligence have revolutionized our understanding of protein dynamics. Nuclear magnetic resonance spectroscopy provides atomic-resolution insights, while molecular simulations offer detailed trajectories motions. Computational methods applied X-ray crystallography cryo-electron microscopy (cryo-EM) enabled the exploration dynamics, capturing ensembles that were previously unattainable. The integration machine learning, exemplified by AlphaFold2, has accelerated structure prediction analysis. These approaches revealed importance allosteric regulation, enzyme catalysis, intrinsically disordered proteins. shift towards ensemble representations structures application single-molecule techniques further enhanced ability capture dynamic nature Understanding is essential for elucidating mechanisms, designing drugs, developing novel biocatalysts, marking significant paradigm structural biology drug discovery.

Language: Английский

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The Expanding Universe of Extensions and Tails: Ribosomal Proteins and Histones in RNA and DNA Complex Signaling and Dynamics

Genes, Journal Year: 2025, Volume and Issue: 16(1), P. 45 - 45

Published: Jan. 1, 2025

This short review bridges two biological fields: ribosomes and nucleosomes—two nucleoprotein assemblies that, along with many viruses, share proteins featuring long filamentous segments at their N- or C-termini. A central hypothesis is that these extensions tails perform analogous functions in both systems. The evolution of structures appears closely tied to the emergence regulatory networks signaling pathways, facilitating increasingly complex roles for nucleosome alike. begins by summarizing nucleosomes, followed a detailed comparison highlighting similarities differences, particularly light recent findings on ribosomal ribosome dynamics. analysis seeks uncover whether systems operate based shared principles mechanisms. nucleosome–ribosome analogy may offer valuable insights into unresolved questions fields. For instance, new structural from might shed potential motifs formed histone tails. From an evolutionary perspective, this study revisits origins regulation ancient assemblies, suggesting represent remnants earliest network governing dynamic control.

Language: Английский

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Familial Oculoauriculovertebral Spectrum: A Genomic Investigation of Autosomal Dominant Inheritance

The Cleft Palate-Craniofacial Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Objective Oculoauriculovertebral spectrum (OAVS) encompasses abnormalities on derivatives from the first and second pharyngeal arches including macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular, vertebral anomalies. We present genetic findings a 3-generation family affected with tags ptosis following an autosomal dominant pattern. Design generated whole-genome sequencing data for proband, father, unaffected paternal grandmother followed by Sanger 23 members top candidate gene mutations. performed parent sibling-based transmission disequilibrium tests (TDTs) burden analysis via penalized linear mixed model, segregation mutation burden, respectively. Next, bioinformatic tools we predicted protein function, pathogenicity, pathway enrichment to investigate biological relevance of mutations identified. Results Rare missense in SIX1, KDR/VEGFR2, PDGFRA showed best OAVS phenotypes this family. When considering any 3 as outcome, SIX1 had strongest associations parent-TDTs sib-TDTs ( P = 0.025, 0.052) (unadjusted P-values). Burden identified (RC 0.87) 0.98) strongly associated severity. Using phenotype-specific outcomes, uni- or bilateral 0.049) ear 0.01), KDR/VEGFR2 (both < 0.01). Conclusion PDGFRA, are phenotypes. has been previously malformations is co-expressed EYA1 during development. Efforts strengthen genotype-phenotype co-relation underlying key discover etiology, counseling, prevention.

Language: Английский

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Factors responsible for alpha-Synuclein aggregation

Progress in molecular biology and translational science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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TMEM160 Promotes Tumor Growth in Lung Adenocarcinoma and Cervical Adenocarcinoma Cell Lines

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1097 - 1097

Published: Jan. 27, 2025

The Chromosome-Centric Human Proteome Project (C-HPP) is an international initiative. It aims to create a protein list expressed in human cells by each chromosomal and mitochondrial DNA enhance our understanding of disease mechanisms, akin the gene generated Genome Project. Transmembrane 160 (TMEM160) member transmembrane proteins (TMEM) family. TMEM have been implicated cancer-related processes, including cell proliferation, migration, epithelial-mesenchymal transition, metastasis, resistance chemotherapy radiotherapy. This study aimed investigate role TMEM160 non-small lung cancer cervical using lines, clinical samples, xenograft studies. Our findings demonstrated that knockdown decreased proliferation lines. We observed localized nucleus cytoplasm dynamic localization during mitosis discovered novel interaction between nuclear such as NUP50. Furthermore, interactome was enriched processes associated with apical junctions, xenobiotic metabolism, glycolysis, reactive oxygen species, UV response DNA, P53 pathway, mitotic spindle. provides initial function progression clarifies need continue investigating participation these cancers.

Language: Английский

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Site-selective photo-crosslinking for the characterisation of transient ubiquitin-like protein-protein interactions

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0316321 - e0316321

Published: Jan. 27, 2025

Non-covalent protein-protein interactions are one of the most fundamental building blocks in cellular signalling pathways. Despite this, they have been historically hard to identify using conventional methods due their often weak and transient nature. Using genetic code expansion incorporation commercially available unnatural amino acids, we developed a highly accessible method whereby between biotinylated ubiquitin-like protein (UBL) probes binding partners can be stabilised ultraviolet (UV) light-induced crosslinks. The complexes purified affinity purification identified by mass spectrometry. resultant covalent bonds withstand even harshest washing conditions, allowing for removal indirect binders whilst retaining capturing interactors that commonly lost during wash steps. This technique is widely applicable effective identifying site-selective non-covalent interactors. Members our team previously demonstrated benefit this small modifier (SUMO). Here, provide further proof-of-principle validation highlight its generality applying an optimised workflow lesser studied UBL, interferon stimulated gene 15 (ISG15). We show able capture known ISG15 from complex mixture manner, only proteins specifically interact with region where acid was incorporated. exquisite degree sensitivity specificity greatly improves upon previous screens aimed at downstream binders, or readers, ISG15. Taken together, approach opens possibility characterising undetected interactions, potential elucidating molecular mechanisms behind poorly understood processes cell.

Language: Английский

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Acetylation of Short Glycopeptides Enables Phase Separation

Biomacromolecules, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

Liquid-liquid phase separation (LLPS) of biomacromolecules is crucial for regulating cellular functions. To explore their molecular mechanisms, peptide-based coacervates mimicking natural proteins have been developed, but the role side chain modifications such as glycosylation remains underexplored. Here, we demonstrate that acetylation short glycopeptides can induce pH- and concentration-dependent separation, while removing acetyl groups abolishes this behavior. Circular dichroism spectroscopy revealed a strong link between peptide structural ordering propensity. Peptides capable forming liquid droplets displayed significant ellipticity change at 205 nm upon changing solution pH. Moreover, these interact with cells enhance antiproliferative property doxorubicin. Therefore, work highlights critical O-acetylation in LLPS provides valuable tool studying parameters its implications processes.

Language: Английский

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Effects of Sup35 overexpression on the formation, morphology, and physiological functions of intracellular Sup35 assemblies

Applied and Environmental Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

ABSTRACT The yeast prion protein Sup35 is aggregation-prone at high concentrations. De novo formation occurs a significantly increased rate after transient overexpression of in the presence another prion, [ PIN + ], but it still rare event. Recent studies uncovered an additional and seemingly more prevalent role Sup35: its physiological level, undergoes phase separation to form reversible condensates response stress. Stress-induced condensation psi - ] strain enhances cellular fitness stress ceases, whereas irreversible aggregates PSI do not confer this advantage. However, how overexpression, which could potentially lead aggregation, affects under conditions remains unclear. In study, we used combinatorial method examine different levels overproduction affect nature, formation, physical properties assemblies cells, as well their impacts on growth. We observed notable morphological distinctions between condensates, possibly indicating mechanisms. addition, aggregation caused by very level can strongly inhibit cell growth, diminish stress-induced when completely aggregated, impair recovery from Together, study advances our fundamental understanding mechanism conclude that vivo are sensitive assembly routes functions. IMPORTANCE living cells often studied overexpression. For role, be problematic. Overexpression shift functions, thereby changing system also behavior shifting position underlying diagram. Our detailed S. cerevisiae shows interplay these factors highlights basic features intracellular such balance localization responsiveness depend levels. apply super-resolution microscopy highlight details within cells.

Language: Английский

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