AlphaFold2 models indicate that protein sequence determines both structure and dynamics

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Июнь 23, 2022

AlphaFold 2 (AF2) has placed Molecular Biology in a new era where we can visualize, analyze and interpret the structures functions of all proteins solely from their primary sequences. We performed AF2 structure predictions for various protein systems, including globular proteins, multi-domain protein, an intrinsically disordered (IDP), randomized two larger (> 1000 AA), heterodimer homodimer complex. Our results show that along with three dimensional (3D) structures, also decodes sequences into residue flexibilities via both predicted local distance difference test (pLDDT) scores models, aligned error (PAE) maps. PAE maps are correlated variation (DV) matrices molecular dynamics (MD) simulations, which reveals predict dynamical nature residues. Here, introduce AF2-scores, simply derived pLDDT range [0, 1]. found most large complexes, AF2-scores highly root mean square fluctuations (RMSF) calculated MD simulations. However, IDP do not correlate RMSF MD, especially IDP. indicate by convey information flexibility, i.e., dynamics.

Язык: Английский

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Cryo-EM of Helical Polymers

Chemical Reviews, Год журнала: 2022, Номер 122(17), С. 14055 - 14065

Опубликована: Фев. 8, 2022

While the application of cryogenic electron microscopy (cryo-EM) to helical polymers in biology has a long history, due huge number macromolecular assemblies viruses, bacteria, archaea, and eukaryotes, use cryo-EM study synthetic soft matter noncovalent been much more limited. This mainly lack familiarity with materials science chemistry communities, contrast fact that was developed as biological technique. Nevertheless, relatively few structures self-assembled peptide nanotubes ribbons solved at near-atomic resolution by have demonstrated should be method choice for structural analysis filaments. In addition, also self-assembly enormous potential polymorphism, something may obscured techniques such scattering spectroscopy. These revealed how far we currently are from being able predict structure these their chaotic behavior.

Язык: Английский

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Imaging Amyloid‐β Membrane Interactions: Ion‐Channel Pores and Lipid‐Bilayer Permeability in Alzheimer's Disease

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(25)

Опубликована: Март 6, 2023

The accumulation of the amyloid-β peptides (Aβ) is central to development Alzheimer's disease. mechanism by which Aβ triggers a cascade events that leads dementia topic intense investigation. self-associates into series complex assemblies with different structural and biophysical properties. It interaction these oligomeric, protofibril fibrillar lipid membranes, or membrane receptors, results in permeability loss cellular homeostasis, key event disease pathology. can have an array impacts on reports included: carpeting effect; detergent ion-channel pore formation. Recent advances imaging interactions are providing clearer picture induced disruption. Understanding relationship between structures will inform therapeutics targeting cytotoxicity.

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 insights into acidic heating-induced amyloid fibrils derived from soy protein as a function of protein concentration

Food Hydrocolloids, Год журнала: 2023, Номер 145, С. 109085 - 109085

Опубликована: Июль 15, 2023

Язык: Английский

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Structural Identification of Individual Helical Amyloid Filaments by Integration of Cryo-Electron Microscopy-Derived Maps in Comparative Morphometric Atomic Force Microscopy Image Analysis

Journal of Molecular Biology, Год журнала: 2022, Номер 434(7), С. 167466 - 167466

Опубликована: Янв. 22, 2022

The presence of amyloid fibrils is a hallmark more than 50 human disorders, including neurodegenerative diseases and systemic amyloidoses. A key unresolved challenge in understanding the involvement disease to explain relationship between individual structural polymorphs fibrils, potentially mixed populations, specific pathologies with which they are associated. Although cryo-electron microscopy (cryo-EM) solid-state nuclear magnetic resonance (ssNMR) spectroscopy methods have been successfully employed recent years determine structures high resolution detail, rely on ensemble averaging fibril entire sample or significant subpopulations. Here, we report method for identification imaged by atomic force (AFM) integration high-resolution maps determined cryo-EM comparative AFM image analysis. This approach was demonstrated using hitherto structurally formed vitro from fragment tau (297–391), termed ‘dGAE’. Our established unequivocally that dGAE bear no heparin-induced vitro. Furthermore, our analysis resulted prediction closely related paired helical filaments (PHFs) isolated Alzheimer’s (AD) brain tissue characterised cryo-EM. These results show utility particle AFM, provide workflow how data can be incorporated into facilitate an integrated polymorphism.

Язык: Английский

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Rational design of functional amyloid fibrillar assemblies

Chemical Society Reviews, Год журнала: 2023, Номер 52(14), С. 4603 - 4631

Опубликована: Янв. 1, 2023

This review highlights the design principles for functional amyloid fibrillar assemblies from an engineering perspective as well through lens of structural insights.

Язык: Английский

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Spectral Fluorescence Pathology of Protein Misfolding Disorders

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(5), С. 898 - 908

Опубликована: Фев. 26, 2024

Protein misfolding has been extensively studied in the context of neurodegenerative disorders and systemic amyloidoses. Due to aggregation proteins being highly heterogeneous generating a variety structures, growing body evidence illustrates numerous ways how aggregates contribute progression diseases such as Alzheimer's disease, Parkinson's prion disorders. Different misfolded species same protein, commonly referred strains, appear play significant role shaping disease clinical phenotype progression. The distinct toxicity profiles various underscore their importance. Current diagnostics struggle differentiate among these strains early course. This review explores potential spectral fluorescence approaches illuminate complexities protein pathology discusses applications advanced methods detection characterization By examining spectrally variable probes, current data analysis approaches, important considerations for use techniques, this aims provide an overview progress made field highlights directions future research.

Язык: Английский

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AlphaFold2 models indicate that protein sequence determines both structure and dynamics

Research Square (Research Square), Год журнала: 2022, Номер unknown

Опубликована: Май 18, 2022

Abstract AlphaFold 2 (AF2) has placed Molecular Biology in a new era where we can visualize, analyze and interpret the structures functions of all proteins solely from their primary sequences. We performed AF2 structure predictions for various protein systems, including globular proteins, multi-domain protein, an intrinsically disordered (IDP), randomized two larger (> 1000 AA), heterodimer homodimer complex. Our results show that along with three dimensional (3D) structures, also decodes sequences into residue flexibilities via both predicted local distance difference test (pLDDT) scores models, aligned error (PAE) maps. PAE maps are correlated variation (DV) matrices molecular dynamics (MD) simulations, which reveals predict dynamical nature residues. Here, introduce AF2-scores, simply derived pLDDT range [0, 1]. found good multisequence alignment (MSA) depths, large complexes, AF2-scores highly root mean square fluctuations (RMSF) calculated MD simulations. For little or no MSA hits (the IDP protein), do not correlate RMSF MD, especially (IDPs). indicate by convey information flexibility, i.e., dynamics.

Язык: Английский

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Structural polymorphism of the low-complexity C-terminal domain of TDP-43 amyloid aggregates revealed by solid-state NMR

Frontiers in Molecular Biosciences, Год журнала: 2023, Номер 10

Опубликована: Март 29, 2023

Aberrant aggregation of the transactive response DNA-binding protein (TDP-43) is associated with several lethal neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Cytoplasmic neuronal inclusions TDP-43 are enriched in various fragments low-complexity C-terminal domain different neurotoxicity. Here we dissect structural basis polymorphism using magic-angle spinning solid-state NMR spectroscopy combination electron microscopy Fourier-transform infrared spectroscopy. We demonstrate that fragments, namely TDP-13 (TDP-43300-414), TDP-11 (TDP-43300-399), TDP-10 (TDP-43314-414), adopt distinct polymorphic structures their amyloid fibrillar state. Our work demonstrates removal less than 10% sequence at N- C-termini generates fibrils comparable macroscopic features but local arrangement. It highlights assembly mechanism TDP-43, addition to hydrophobic region, also driven by complex interactions involving aggregation-prone segments a potential source polymorphism.

Язык: Английский

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