NLRP3 inflammasome in neurodegenerative disease

Translational research, Год журнала: 2022, Номер 252, С. 21 - 33

Опубликована: Авг. 9, 2022

Язык: Английский

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AlphaFold 2 and NMR Spectroscopy: Partners to Understand Protein Structure, Dynamics and Function

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Май 17, 2022

The artificial intelligence program AlphaFold 2 is revolutionizing the field of protein structure determination as it accurately predicts 3D two thirds human proteome. Its predictions can be used directly structural models or indirectly aids for experimental using X-ray crystallography, CryoEM NMR spectroscopy. Nevertheless, neither afford insight into how proteins fold, nor determine stability dynamics. Rare folds minor alternative conformations are also not predicted by and does forecast impact post translational modifications, mutations ligand binding. remaining third proteome which poorly largely corresponds to intrinsically disordered regions proteins. Key regulation signaling networks, these often form biomolecular condensates amyloids. Fortunately, limitations complemented This approach provides information on folding dynamics well amyloids their modulation conditions, small molecules, mutations, flanking sequence, interactions with other proteins, RNA virus. Together, spectroscopy collaborate advance our comprehension

Язык: Английский

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Cryo-EM structures of prion protein filaments from Gerstmann–Sträussler–Scheinker disease

Acta Neuropathologica, Год журнала: 2022, Номер 144(3), С. 509 - 520

Опубликована: Июль 12, 2022

Prion protein (PrP) aggregation and formation of PrP amyloid (APrP) are central events in the pathogenesis prion diseases. In dominantly inherited amyloidosis known as Gerstmann-Sträussler-Scheinker (GSS) disease, plaques made present throughout brain. The c.593t > c mutation gene (PRNP) results a phenylalanine to serine amino acid substitution at residue 198 (F198S) causes most severe among GSS variants. It has been shown that neurodegeneration this disease is associated with presence extracellular APrP neuronal intracytoplasmic Tau inclusions, have contain paired helical filaments identical those found Alzheimer disease. Using cryogenic electron microscopy (cryo-EM), we determined for first time structures human APrP, isolated post-mortem from brain two symptomatic PRNP F198S carriers. We report composed dimeric, trimeric tetrameric left-handed protofilaments their protomers sharing common fold. cross-β spines consist 62 acids span glycine 80 141, adopting previously unseen spiral fold thicker outer layer thinner inner layer. Each protomer comprises nine short β-strands, β1 β8 strands, well β4 β9 forming steric zipper. data obtained by cryo-EM provide insights into structural complexity filament amyloidosis. novel findings highlight urgency extending our knowledge filaments' may underlie distinct clinical pathologic phenotypes neurodegenerative

Язык: Английский

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High-throughput cryo-EM structure determination of amyloids

Faraday Discussions, Год журнала: 2022, Номер 240, С. 243 - 260

Опубликована: Янв. 1, 2022

This paper presents new cryo-EM image processing methods for amyloids, including automated picking and strategies helical structure determination in RELION. The shows examples of tau filament structures that were solved using these methods.

Язык: Английский

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Structural evolution of fibril polymorphs during amyloid assembly

Cell, Год журнала: 2023, Номер 186(26), С. 5798 - 5811.e26

Опубликована: Дек. 1, 2023

Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in is unknown. Consequently, whether different architectures, potentially pathological properties, form during remains Here, we used cryo-EM determine at times vitro fibrillation a disease-related variant human islet polypeptide (IAPP-S20G). Strikingly, lag, growth, plateau phases have new forms appearing others disappearing as proceeds. A time course wild-type hIAPP also shows changing time, suggesting that this general property IAPP assembly. The observation transiently populated implications for understanding mechanisms potential progression

Язык: Английский

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Structural analysis and architectural principles of the bacterial amyloid curli

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Май 17, 2023

Abstract Two decades have passed since the initial proposition that amyloids are not only (toxic) byproducts of an unintended aggregation cascade, but they can also be produced by organism to serve a defined biological function. That revolutionary idea was borne out realization large fraction extracellular matrix holds Gram-negative cells into persistent biofilm is composed protein fibers (curli; tafi) with cross-β architecture, nucleation-dependent polymerization kinetics and classic amyloid tinctorial properties. The list proteins shown form so-called functional in vivo has greatly expanded over years, detailed structural insights followed at similar pace part due associated experimental barriers. Here we combine extensive AlphaFold2 modelling cryo-electron transmission microscopy propose atomic model curli protofibrils, their higher modes organization. We uncover unexpected diversity building blocks fibril architectures. Our results allow for rationalization extreme physico-chemical robustness curli, as well earlier observations inter-species promiscuity, should facilitate further engineering efforts expand repertoire curli-based materials.

Язык: Английский

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Cryo‐EM structures of tau filaments from SH‐SY5Y cells seeded with brain extracts from cases of Alzheimer's disease and corticobasal degeneration

FEBS Open Bio, Год журнала: 2023, Номер 13(8), С. 1394 - 1404

Опубликована: Июнь 20, 2023

The formation of amyloid filaments through templated seeding is believed to underlie the propagation pathology in most human neurodegenerative diseases. A widely used model system study this process seed filament cultured cells using brain extracts. Here, we report electron cryo‐microscopy structures tau from undifferentiated seeded SH‐SY5Y that transiently expressed N‐terminally HA‐tagged 1N3R or 1N4R tau, extracts individuals with Alzheimer's disease corticobasal degeneration. Although resulting differed those seeds, some degrees structural templating were observed. Studying cells, and determining filaments, can thus provide insights into cellular aspects underlying

Язык: Английский

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Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Окт. 5, 2023

Mice transgenic for human mutant P301S tau are widely used as models tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of four-repeat tau. Here we electron cryo-microscopy (cryo-EM) to determine the structures filaments from brains Tg2541 PS19 mice. Both lines express (0N4R 1N4R PS19) on mixed genetic backgrounds downstream different promoters (murine Thy1 murine Prnp PS19). The mice differ each other those wild-type brains. humans with mutations P301L, or P301T in MAPT not known. Filaments share a substructure at junction repeats 2 3, which comprises residues I297-V312 includes mutation. filament core brainstem consists K274-H329 two disconnected protein densities. Two non-proteinaceous densities also evidence. cerebral cortex line extends G271-P364 One strong density is present. Unlike brains, sequences following repeat 4 missing cores

Язык: Английский

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Identical tau filaments in subacute sclerosing panencephalitis and chronic traumatic encephalopathy

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Май 5, 2023

Subacute sclerosing panencephalitis (SSPE) occurs in some individuals after measles infection, following a symptom-free period of several years. It resembles chronic traumatic encephalopathy (CTE), which happens repetitive head impacts or exposure to blast waves, period. As CTE, the neurofibrillary changes SSPE are concentrated superficial cortical layers. Here we used electron cryo-microscopy (cryo-EM) tau filaments from two cases show that folds and CTE identical. Two types were each made identical protofilaments with an extra density β-helix region. Like vast majority Type I, minority II filaments. These findings suggest fold can be caused by different environmental insults, may linked inflammatory changes.

Язык: Английский

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Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(7), С. 3926 - 3936

Опубликована: Фев. 8, 2023

The aggregation of tau into insoluble fibrils is a defining feature neurodegenerative tauopathies. However, has positive overall charge and highly soluble; so, polyanions, such as heparin, are typically required to promote its in vitro. There dozens polyanions living systems, it not clear which ones might this process. Here, we systematically measure the ability 37 diverse, anionic biomolecules initiate using either wild-type (WT) or disease-associated P301S mutant. We find that from many different structural classes can fibril formation sensitive greater number (28/37) than WT (21/37). also some preferentially reduce lag time reactions, while others enhance elongation rate, suggesting they act on partially distinct steps. From resulting structure–activity relationships, valency polyanion seems be an important chemical anions with low tend weaker inducers, even at same charge. Finally, identity influences morphology based electron microscopy limited proteolysis. These results provide insights crucial role polyanion–tau interactions modulating conformational dynamics implications for understanding landscape complex cellular environment.

Язык: Английский

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