Coacervates Composed of Low‐Molecular‐Weight Compounds– Molecular Design, Stimuli Responsiveness, Confined Reaction

Advanced Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

The discovery of coacervation within living cells through liquid-liquid phase separation has inspired scientists to investigate its fundamental principles and significance. Indeed, coacervates composed low-molecular-weight compounds based on supramolecular strategy can offer valuable models for biomolecular condensates useful tools. This mini-review highlights recent findings advances in (artificial condensates), primarily compounds, with focuses their molecular design, stimuli responsiveness, controlled reactions or leading the coacervates.

Язык: Английский

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Long non‐coding RNAs as key regulators of neurodegenerative protein aggregation

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(2)

Опубликована: Фев. 1, 2025

Abstract The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated the pathological processes of different NDDs, process misfolding aggregation remains notably similar across various conditions. Specifically, undergo into beta‐folded (β‐folded) conformation, resulting formation insoluble amyloid proteins. Despite advancements comprehending certain facets this intricate remain incompletely elucidated. In recent years, concept that long non‐coding RNAs (lncRNAs) contribute to has gained recognition. LncRNAs influence aggregates by facilitating overexpression through regulation gene transcription translation, inhibiting degradation via lysosomal autophagic pathways, targeting aberrant modifications phase transitions A better understanding relationship between lncRNAs is an important step dissecting underlying molecular mechanisms will discovery new therapeutic targets strategies. Highlights NDDs marked leading dysfunction loss function. being involved β‐folded conformations forming consistent role attention, as they regulate inhibit degradation, target modifications. Understanding link crucial for uncovering developing targets.

Язык: Английский

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Probing Noncovalent Interactions by Fast Magic‐Angle Spinning NMR at 100 kHz and More

ChemPhysChem, Год журнала: 2024, Номер unknown

Опубликована: Авг. 12, 2024

Abstract Noncovalent interactions are the basis for a large number of chemical and biological molecular‐recognition processes, such as those occurring in supramolecular chemistry, catalysis, solid‐state reactions mechanochemistry, protein folding, protein‐nucleic acid binding, biomolecular phase separation processes. In this perspective article, some recent developments probing noncovalent by proton‐detected Nuclear Magnetic Resonance (NMR) spectroscopy at Magic‐Angle Spinning (MAS) frequencies 100 kHz more reviewed. The development MAS rotors with decreasing outer diameters, combined superconducting magnets operating high static magnetic‐field strengths up to 28.2 T (1200 MHz proton Larmor frequency) improves resolution sensitivity NMR, which is fundamental requirement shedding light on solids. examples reported article range from binding ATP‐fueled motor proteins hydrogen‐π interaction calixarene‐lanthanide complex.

Язык: Английский

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Deciphering the Seed Size-Dependent Cellular Internalization Mechanism for α-Synuclein Fibrils

Biochemistry, Год журнала: 2025, Номер 64(2), С. 377 - 400

Опубликована: Янв. 6, 2025

Aggregation of α-synuclein (α-Syn) and Lewy body (LB) formation are the key pathological events implicated in Parkinson's disease (PD) that spread a prion-like manner. However, biophysical structural characteristics toxic α-Syn species molecular drive early propagation amyloids manner remain elusive. We used neuronal cell model to demonstrate size-dependent native biological activities fibril seeds. Biophysical characterization seeds generated by controlled fragmentation indicated increased leads reduction size, correlating directly with extent events. Although size-based complexity amyloid fibrils modulates their amplification pathways, it remains unclear how variability seed size dictates its specific uptake mechanism into cells. The present study elucidates internalization is regulated Further, we endocytic pathways (dynamin-dependent clathrin/caveolin-mediated) more prominent for differential short compared longer counterparts. This preference might contribute enhanced transcellular Overall, suggests physical dimension significantly influences cellular responses initiation progression PD.

Язык: Английский

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Catalytic Assembly of Peptides Mediated by Complex Coacervates

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

The assembly of peptides is generally mediated by liquid–liquid phase separation, which enables control over kinetics, final structure, and functions peptide-based supramolecular materials. Modulating separation can alter the kinetics changing solvents or introducing external fields. Herein, we demonstrate that be effectively catalyzed complex coacervates. negatively charged sodium alginate (SA) form coacervates with positively KLVFFAE (Aβ16–22, abbreviated as KE) peptide, thereby lowering nucleation barrier promoting peptide. As binding affinity SA-KE dosage SA decrease, system shifts from a relatively inefficient template-induced to highly efficient catalytic before ultimately reverting slow spontaneous assembly. Therefore, both well stoichiometry do not follow intuitive rule "more better", but rather there exists an optimal value maximizes rate

Язык: Английский

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Functional Biomaterials Derived from Protein Liquid–Liquid Phase Separation and Liquid‐to‐Solid Transition

Advanced Materials, Год журнала: 2025, Номер unknown

Опубликована: Фев. 9, 2025

Protein phase transitions play a vital role in both cellular functions and pathogenesis. Dispersed proteins can undergo liquid-liquid separation to form condensates, process that is reversible highly regulated within cells. The formation physicochemical properties of these such as composition, viscosity, multiphase miscibility, are precisely modulated fulfill specific biological functions. However, protein condensates further liquid-to-solid state, forming β-sheet-rich aggregates may disrupt function lead diseases. While this phenomenon crucial for processes has significant implications neurodegenerative diseases, the behavior naturally derived or engineered polypeptides also presents opportunities developing high-performance, multifunctional materials at various scales. Additionally, unique molecular recruitment capabilities inspire innovative advancements biomaterial design applications drug discovery, delivery, biosynthesis. This work highlights recent progress understanding mechanisms underlying behavior, particularly how it responds internal changes external physical stimuli. Furthermore, fabrication from diverse sources through controlled demonstrated.

Язык: Английский

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Polyphosphate Discriminates Protein Conformational Ensembles More Efficiently than DNA Promoting Diverse Assembly and Maturation Behaviors

Опубликована: Март 4, 2025

Disordered proteins and domains often assemble into condensates with polyanionic nucleic acids, primarily via charge complementarity, regulating numerous cellular functions. However, the assembly mechanisms associated other abundant ubiquitous, anionic, stress-response polymer, polyphosphate (polyP), is less understood. Here, we employ intrinsically disordered DNA binding domain (DBD) of cytidine repressor (CytR) from E.coli to study nature processes polyP DNA. CytR forms metastable liquid-like DNA, while undergoing liquid-to-solid transition in former solubilizing latter. On mutationally engineering ensemble exhibit more or structure dimensions than WT, process directed either partial time-dependent solubilization spontaneous aggregation, respectively. hand, variants form only but droplets which solubilize within a few hours. Polyphosphate induces large secondary-structure changes, two mutants adopting polyproline II-like structures droplets, has minimal structural effects. Our findings reveal how can efficiently discern conformational heterogeneity starting protein ensemble, its structure, compactness, broad implications involving stress response bacterial systems.

Язык: Английский

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Polyphosphate Discriminates Protein Conformational Ensembles More Efficiently than DNA Promoting Diverse Assembly and Maturation Behaviors

Опубликована: Март 4, 2025

Disordered proteins and domains often assemble into condensates with polyanionic nucleic acids, primarily via charge complementarity, regulating numerous cellular functions. However, the assembly mechanisms associated other abundant ubiquitous, anionic, stress-response polymer, polyphosphate (polyP), is less understood. Here, we employ intrinsically disordered DNA binding domain (DBD) of cytidine repressor (CytR) from E.coli to study nature processes polyP DNA. CytR forms metastable liquid-like DNA, while undergoing liquid-to-solid transition in former solubilizing latter. On mutationally engineering ensemble exhibit more or structure dimensions than WT, process directed either partial time-dependent solubilization spontaneous aggregation, respectively. hand, variants form only but droplets which solubilize within a few hours. Polyphosphate induces large secondary-structure changes, two mutants adopting polyproline II-like structures droplets, has minimal structural effects. Our findings reveal how can efficiently discern conformational heterogeneity starting protein ensemble, its structure, compactness, broad implications involving stress response bacterial systems.

Язык: Английский

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Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Год журнала: 2025, Номер 4

Опубликована: Март 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Язык: Английский

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Raman spectroscopy and imaging of protein droplet formation and aggregation

Current Opinion in Structural Biology, Год журнала: 2025, Номер 92, С. 103041 - 103041

Опубликована: Апрель 3, 2025

Язык: Английский

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