A complex interplay between various processes underlies the neuropathology of Alzheimer's disease (AD) and its progressive course. Several lines of evidence point to the coupling between Aβ aggregation and neuroinflammation and its role in maintaining brain homeostasis during the long prodromal phase of AD. Little is however known about how this protective mechanism fails and as a result, an irreversible and progressive transition to clinical AD occurs.
View Article and Find Full Text PDFMetal ions, including biologically prevalent sodium ions, can modulate electrostatic interactions frequently involved in the stability of condensed compartments in cells. Quantitative characterization of heterogeneous ion dynamics inside biomolecular condensates demands new experimental approaches. Here we develop a Na NMR relaxation-based integrative approach to probe dynamics of sodium ions inside agarose gels as a model system.
View Article and Find Full Text PDFSignal transduction by the ligated B cell antigen receptor (BCR) depends on the preorganization of its intracellular components, such as the effector proteins SLP65 and CIN85 within phase-separated condensates. These liquid-like condensates are based on the interaction between three Src homology 3 (SH3) domains and the corresponding proline-rich recognition motifs (PRM) in CIN85 and SLP65, respectively. However, detailed information on the protein conformation and how it impacts the capability of SLP65/CIN85 condensates to orchestrate BCR signal transduction is still lacking.
View Article and Find Full Text PDFLiquid water is essential for life as we know it and the coupling between water and biomolecular dynamics is crucial for life processes. Jupiter's moon Europa is a good candidate for searching for extraterrestrial life in our outer solar system, mainly because a liquid water salty ocean in contact with a rocky seafloor underlies its ice shell. Little, however, is known about the chemical composition of the subglacial ocean of Europa or the brine pockets within its ice shell and their impacts on water dynamics.
View Article and Find Full Text PDFLittle is known about how maturation of Alzheimer's disease-related amyloid β (Aβ) fibrils alters their stability and potentially influences their spreading in the brain. Using high-pressure NMR, we show that progression from early to late Aβ40 aggregates enhances the kinetic stability, while ageing during weeks to months enhances their thermodynamic stability.
View Article and Find Full Text PDFAmyloid-beta (Aβ) deposition as senile plaques is a pathological hallmark of Alzheimer's disease (AD). AD is characterized by a large level of heterogeneity in amyloid pathology, whose molecular origin is poorly understood. Here, we employ NMR spectroscopy and MD simulation at ambient and high pressures and investigate how AD-related mutations in Aβ peptide influence the stability of Aβ aggregates.
View Article and Find Full Text PDFReorientational dynamics of intrinsically disordered proteins (IDPs) contain multiple motions often clustered around three motional modes: ultrafast librational motions of amide groups, fast local backbone conformational fluctuations and slow chain segmental motions. This dynamic picture is mainly based on N NMR relaxation studies of IDPs at relatively low temperatures where the amide-water proton exchange rates are sufficiently small. Less is known, however, about the dynamics of IDPs at more physiological temperatures.
View Article and Find Full Text PDFHeparins and heparan sulfate polysaccharides are negatively charged glycosaminoglycans and play important roles in cell-to-matrix and cell-to-cell signaling processes. Metal ion binding to heparins alters the conformation of heparins and influences their function. Various experimental techniques have been used to investigate metal ion-heparin interactions, frequently with inconsistent results.
View Article and Find Full Text PDFNatural compounds with anti-aggregation capacity are increasingly recognized as viable candidates against neurodegenerative diseases. Recently, the polyphenolic fraction of propolis (PFP), a complex bee product, has been shown to inhibit amyloid aggregation of a model protein especially in the nanosheet form. Here, we examine the aggregation-modulating effects of the PFP nanosheets on α-synuclein (α-syn), an intrinsically disordered protein involved in the pathogenesis of Parkinson's disease.
View Article and Find Full Text PDFIn their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our group ( , , 1380-1388; DOI: 10.
View Article and Find Full Text PDFIncreasing the temperature by just a few degrees may lead to structural perturbation or unfolding of the protein and consequent loss of function. The concepts of flexibility and rigidity are fundamental for understanding the relationships between function, structure and stability. Protein unfolding can often be triggered by thermal fluctuations with flexible residues usually on the protein surface.
View Article and Find Full Text PDFLiving cells often contain compartments with high concentration of charged biomolecules. A key question pertinent to the function of biomolecules is how water dynamics are affected by interaction with charged molecules. Here, we study the dynamical behavior of water in an extreme condition, that is, in saturated salt solutions, where nearly all water molecules are located within the first hydration layer of ions.
View Article and Find Full Text PDFBiomolecular phase separation plays a key role in the spatial organization of cellular activities. Dynamic formation and rapid component exchange between phase separated cellular bodies and their environment are crucial for their function. Here, we employ a well-established phase separating model system, namely, a triethylamine (TEA)-water mixture, and develop an NMR approach to detect the exchange of scaffolding TEA molecules between separate phases and determine the underlying exchange rate.
View Article and Find Full Text PDFAlzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on the production of cerebral Aβ. A meta-analysis on humans showed moderate effects in the short term but no improvement in the Alzheimer's Disease Assessment Scale-Cognitive Subscale behavioral test.
View Article and Find Full Text PDFMicrometer-sized objects are widely known to exhibit chemically driven motility in systems away from equilibrium. Experimental observation of reaction-induced motility or enhancement in diffusivity at the much shorter length scale of small molecules is, however, still a matter of debate. Here, we investigate the molecular diffusivity of reactants, catalyst, and product of a model reaction, the copper-catalyzed azide-alkyne cycloaddition click reaction, and develop new NMR diffusion approaches that allow the probing of reaction-induced diffusion enhancement in nanosized molecular systems with higher accuracy than the state of the art.
View Article and Find Full Text PDFSeveral lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer's disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Letter, we combine high-pressure NMR, multiquantum chemical exchange saturation transfer (MQ-CEST) NMR, and microseconds-long molecular dynamics simulation and provide evidence of the presence of several salt bridges between Arg5 and its nearby negatively charged residues, in particular, Asp7 and Glu3.
View Article and Find Full Text PDFThe amyloid cascade hypothesis proposes that amyloid-beta (Aβ) aggregation is the initial triggering event in Alzheimer's disease. Here, we utilize NMR spectroscopy and monitor the structural dynamics of two variants of Aβ, Aβ40 and Aβ42, as a function of temperature. Despite having identical amino acid sequence except for the two additional C-terminal residues, Aβ42 has higher aggregation propensity than Aβ40.
View Article and Find Full Text PDFPhase separation is a fundamental physicochemical process underlying the spatial arrangement and coordination of cellular events. Detailed characterization of biomolecular phase separation requires experimental access to the internal environment of dilute and especially condensed phases at high resolution. In this study, we take advantage from the ubiquitous presence of sodium ions in biomolecular samples and present the potentials of Na NMR as a proxy to report the internal fluidity of biomolecular condensed phases.
View Article and Find Full Text PDFSelectively studying parts of proteins and metabolites in tissue with nuclear magnetic resonance promises new insights into molecular structures or diagnostic approaches. Nuclear spin singlet states allow the selection of signals from chemical moieties of interest in proteins or metabolites while suppressing background signal. This selection process is based on the electron-mediated coupling between two nuclear spins and their difference in resonance frequency.
View Article and Find Full Text PDFWe present an NMR method based on natural abundance 17O relaxation of water to determine effective viscosity in biological aqueous samples. The method accurately captures viscosity of dilute and crowded protein solutions and offers a fairly simple way to quantify the internal fluidity of biological condensates formed through phase separation.
View Article and Find Full Text PDFCells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation.
View Article and Find Full Text PDFAmyloid-β (Aβ) aggregation is a hallmark of Alzheimer's disease. As an intrinsically disordered protein, Aβ undergoes extensive dynamics on multiple length and time scales. Access to a comprehensive picture of the reorientational dynamics in Aβ requires therefore the combination of complementary techniques.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
November 2018
Intrinsically disordered proteins (IDPs) experience a diverse spectrum of motions that are difficult to characterize with a single experimental technique. Herein we combine high- and low-field nuclear spin relaxation, nanosecond fluorescence correlation spectroscopy (nsFCS), and long molecular dynamics simulations of alpha-synuclein, an IDP involved in Parkinson disease, to obtain a comprehensive picture of its conformational dynamics. The combined analysis shows that fast motions below 2 ns caused by local dihedral angle fluctuations and conformational sampling within and between Ramachandran substates decorrelate most of the backbone N-H orientational memory.
View Article and Find Full Text PDFThe protein α-synuclein (αSN) aggregates to form fibrils in neuronal cells of Parkinson's patients. Here we report on the effect of neutral (zwitterionic) nanoliposomes (NLPs), supplemented with cholesterol (NLP-Chol) and decorated with PEG (NLP-Chol-PEG), on αSN aggregation and neurotoxicity. Both NLPs retard αSN fibrillization in a concentration-independent fashion.
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