A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease

Chemical Science, Journal Year: 2023, Volume and Issue: 14(35), P. 9427 - 9438

Published: Jan. 1, 2023

Ferroptosis, an iron-dependent cell death, plays a crucial role in the pathology of Alzheimer's disease (AD). Several characteristics AD, including excessive iron accumulation, elevated lipid peroxide and reactive oxygen species (ROS) levels, decreased glutathione peroxidase 4 (GPX4) align with features ferroptosis. While traditional methods inhibiting ferroptosis have centered on chelating Fe trapping radicals, therapeutic strategies that modulate GPX4 axis to mitigate AD are yet be explored. This report introduces naturally occurring polyphenols (PPs) as dual-acting agents synergistically alleviate AD. The mechanisms action encompass modulation amyloid tau cascade, reduction oxidative stress, mitochondrial rescue, inhibition For first time, we show single multifunctional molecule, tannic acid (TA) binds at activator site GPX4, augmenting both its activity cellular providing conceptually innovative integrated approach for treating via GPX4-ferroptosis axis. ability TA enhance levels under conditions opens up newer promising avenues combating crosstalk between

Language: Английский

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IDPConformerGenerator: A Flexible Software Suite for Sampling the Conformational Space of Disordered Protein States

The Journal of Physical Chemistry A, Journal Year: 2022, Volume and Issue: 126(35), P. 5985 - 6003

Published: Aug. 28, 2022

The power of structural information for informing biological mechanisms is clear stable folded macromolecules, but similar structure-function insight more difficult to obtain highly dynamic systems such as intrinsically disordered proteins (IDPs) which must be described ensembles. Here, we present IDPConformerGenerator, a flexible, modular open-source software platform generating large and diverse ensembles protein states that builds conformers obey geometric, steric, other physical restraints on the input sequence. IDPConformerGenerator samples backbone phi (φ), psi (ψ), omega (ω) torsion angles relevant sequence fragments from loops secondary structure elements extracted structures in RCSB Protein Data Bank side chains robust Monte Carlo algorithms using expanded rotamer libraries. has many user-defined options enabling variable fractional sampling structures, supports Bayesian models assessing agreement IDP consistency with experimental data, introduces machine learning approach transform between internal Cartesian coordinates reduced error. will facilitate characterization ultimately provide insights into these have key functions.

Language: Английский

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Driving forces behind phase separation of the carboxy-terminal domain of RNA polymerase II

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 25, 2023

Abstract Eukaryotic gene regulation and pre-mRNA transcription depend on the carboxy-terminal domain (CTD) of RNA polymerase (Pol) II. Due to its highly repetitive, intrinsically disordered sequence, CTD enables clustering phase separation Pol The molecular interactions that drive II are unclear. Here, we show multivalent involving tyrosine impart temperature- concentration-dependent self-coacervation CTD. NMR spectroscopy, ensemble calculations all-atom dynamics simulations demonstrate presence diverse tyrosine-engaging interactions, including tyrosine-proline contacts, in condensed states human other low-complexity proteins. We further network is responsible for co-recruitment Mediator complex during separation. Our work advances understanding driving forces thus provides basis better understand CTD-mediated eukaryotic transcription.

Language: Английский

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Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation

JACS Au, Journal Year: 2023, Volume and Issue: 3(3), P. 834 - 848

Published: Feb. 24, 2023

Biomolecular condensation is involved in various cellular processes; therefore, regulation of crucial to prevent deleterious protein aggregation and maintain a stable environment. Recently, class highly charged proteins, known as heat-resistant obscure (Hero) was shown protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero remain unknown. In this study, we performed multiscale dynamics (MD) simulations Hero11, protein, C-terminal low-complexity domain (LCD) transactive response DNA-binding 43 (TDP-43), under conditions examine their interactions with each other. We found that Hero11 permeates into condensate formed LCD TDP-43 (TDP-43-LCD) induces changes conformation, intermolecular interactions, TDP-43-LCD. also examined possible structures atomistic coarse-grained MD higher fraction disordered region tends assemble on surface condensates. Based simulation results, have proposed three for Hero11's regulatory function: (i) dense phase, TDP-43-LCD reduces contact shows faster diffusion decondensation due repulsive Hero11-Hero11 interactions. (ii) dilute saturation concentration increased, its conformation relatively more extended variant, induced attractive Hero11-TDP-43-LCD (iii) small condensates can contribute avoiding fusion The provide new insights biomolecular cells conditions.

Language: Английский

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Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease

Redox Biology, Journal Year: 2024, Volume and Issue: 71, P. 103119 - 103119

Published: March 11, 2024

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form cell death plays significant role in multifaceted AD pathogenesis through generation reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, reduction glutathione peroxidase 4 (GPX4) enzyme activity levels. Aberrant liquid-liquid phase separation (LLPS) tau drives growth maturation NFTs contributing to pathogenesis. In this study, we strategically combined structural functional properties gallic acid (GA) cyclic dipeptides (CDPs) synthesize hybrid molecules that effectively target both ferroptosis toxicity AD. This innovative approach marks paradigm shift from conventional therapeutic strategies. first report synthetic small molecule (GCTR) combats ferroptosis, simultaneously restoring enzymatic enhancing cellular levels its master regulator, GPX4. Further, GCTR disrupts Fe3+-induced LLPS tau, aids attenuation abnormal fibrillization. The synergistic action combating toxicity, bolstered GPX4 enhancement modulation LLPS, holds promise for development molecule-based novel therapeutics

Language: Английский

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Network of hotspot interactions cluster tau amyloid folds

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 16, 2023

Abstract Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a can adopt diversity folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method estimate relative energetic contribution each amino acid amyloid assembly. We apply our twenty-seven ex vivo vitro fibril structural polymorphs microtubule-associated tau. uncover networks energetically important interactions involving amyloid-forming motifs that stabilize different folds. evaluate predictions cellular aggregation assays. Using machine learning approach, classify structures based on residue energetics identify distinguishing unifying features. Our profiling suggests minimal sequence elements control stability tau fibrils, allowing future design sequences fold unique

Language: Английский

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Structural ensembles of disordered proteins from hierarchical chain growth and simulation

Current Opinion in Structural Biology, Journal Year: 2022, Volume and Issue: 78, P. 102501 - 102501

Published: Dec. 1, 2022

Disordered proteins and nucleic acids play key roles in cellular function disease. Here, we review recent advances the computational exploration of conformational dynamics flexible biomolecules. While atomistic molecular (MD) simulation has seen a lot improvement years, large-scale computing resources careful validation are required to simulate full-length disordered biopolymers solution. As computationally efficient alternative, hierarchical chain growth (HCG) combines pre-sampled fragments statistically reproducible manner into ensembles atomically detailed biomolecular structures. Experimental data can be integrated during after assembly. Applications neurodegeneration-linked α-synuclein, tau, TDP-43, including as condensate, illustrate use HCG. We conclude by highlighting emerging connections AI-based structural modeling AlphaFold2.

Language: Английский

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Hierarchical Assembly of Single-Stranded RNA

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(5), P. 2246 - 2260

Published: Feb. 16, 2024

Single-stranded RNA (ssRNA) plays a major role in the flow of genetic information–most notably, form messenger (mRNA)–and regulation biological processes. The highly dynamic nature chains unpaired nucleobases challenges structural characterizations ssRNA by experiments or molecular dynamics (MD) simulations alike. Here, we use hierarchical chain growth (HCG) to construct ensembles chains. HCG assembles structures protein and nucleic acid from fragment libraries created MD simulations. Applied homo- heteropolymeric ssRNAs different lengths, find that produces overall are good agreement with diverse experiments, including nuclear magnetic resonance (NMR), small-angle X-ray scattering (SAXS), single-molecule Förster energy transfer (FRET). can be further improved ensemble refinement using Bayesian inference (BioEn). also used assemble combine base-paired base-unpaired regions, as illustrated for 5′ untranslated region (UTR) SARS-CoV-2 RNA.

Language: Английский

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FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 23, 2023

Abstract Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia abnormal (FTD-tau), missense mutations in enhance its aggregation propensity. Here we describe structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from vitro, silico and cellular experiments. We find that stabilizes a local hydrophobic cluster which allosterically exposes 306 VQIVYK 311 amyloid motif ; identify suppressor destabilizes S320F-based clustering reversing phenotype vitro cells; computationally engineer spontaneously aggregating sequences through optimizing nonpolar clusters surrounding S320 position. uncover regulating balances contacts long-range interactions sequester motifs. Understanding this process may permit control into polymorphs to aid design reagents targeting disease-specific conformations.

Language: Английский

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Intramolecular structural heterogeneity altered by long-range contacts in an intrinsically disordered protein

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(30)

Published: July 17, 2023

Short-range interactions and long-range contacts drive the 3D folding of structured proteins. The proteins' structure has a direct impact on their biological function. However, nearly 40% eukaryotes proteome is composed intrinsically disordered proteins (IDPs) protein regions that fluctuate between ensembles numerous conformations. Therefore, to understand function, it critical depict how structural ensemble statistics correlate IDPs' amino acid sequence. Here, using small-angle X-ray scattering time-resolved Förster resonance energy transfer (trFRET), we study intramolecular heterogeneity neurofilament low tail domain (NFLt). Using theoretical results polymer physics, find Flory scaling exponent NFLt subsegments correlates linearly with net charge, ranging from ideal self-avoiding chains. Surprisingly, measuring same segments in context whole protein, regardless peptide sequence, segments' are more expanded than when measured independently. Our findings show while physics can, some level, relate IDP's sequence its conformations, distant acids play crucial role determining structures. This emphasizes necessity advanced theories fully describe IDPs hope will allow us model

Language: Английский

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