Interplay of Proteostasis Capacity and Protein Aggregation: Implications for Cellular Function and Disease

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(14), P. 168615 - 168615

Published: May 16, 2024

Eukaryotic cells are equipped with an intricate proteostasis network (PN), comprising nearly 3,000 components dedicated to preserving proteome integrity and sustaining protein homeostasis. This protective system is particularly important under conditions of external intrinsic cell stress, where inherently dynamic proteins may unfold lose functionality. A decline in capacity associated the aging process, resulting a reduced folding efficiency newly synthesized deficit cellular degrade misfolded proteins. critical consequence PN insufficiency accumulation cytotoxic aggregates that underlie various age-related neurodegenerative other pathologies. By interfering specific components, toxic place excessive burden on PN's ability maintain integrity. initiates feed-forward loop, wherein generation aggregated ultimately leads collapse demise.

Language: Английский

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COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, enable more realistic modeling involving domains without additional costs. COCOMO2 was parametrized directly solubility data improve performance predicting concentration-dependent broader range biomolecular systems compared original version. enables new applications study condensates involve IDPs together assembly also provides expanded foundation development multiscale approaches span residue-level atomistic resolution.

Language: Английский

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Hierarchical Engineering for Biopolymer‐based Hydrogels with Tailored Property and Functionality

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Abstract Biopolymer‐based hydrogels offer versatility in biomedical engineering due to their abundance, biocompatibility, tailorable properties, and environmental responsiveness. Realizing full potential requires understanding the molecular‐level design principles that govern macroscopic behavior. This review analyzes recent advances molecular of biopolymer‐based hydrogels, emphasizing innovative network strategies processing methods for precise control over material properties functions. How influences hydrogel behavior across multiple length scales are explored, focusing on: 1) strategies: approaches like double networks, interpenetrating supramolecular assemblies tailor mechanical responsive properties; 2) techniques: such as Hofmeister effect‐induced chain aggregating, cononsolvency‐based porous structure controlling, directional freezing‐induced alignment achieve hierarchical anisotropic structures. these influence critical strength, inner mass transportation, degradation discussed. The also covers advanced fabrication techniques leverage create complex, functional hydrogels. By elucidating relationships between architecture, methods, resulting this work aims provide a framework designing next‐generation with enhanced performance functionality various applications.

Language: Английский

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Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: May 29, 2024

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest genetic basis. This review focuses on SOD1 , the first gene found to be associated with fALS, which has been more recently confirmed genome sequencing. While informative, databases such as ALSoD STRENGTH exhibit regional biases. Through systematic examination mutations from 1993 2023, we different geographic distributions clinical presentations. Even though variants are expressed at protein levels have half-lives dismutase activities, these alterations lead function that not consistently correlated severity. Gain toxic aggregates mutated emerged one key contributors ALS. Therapeutic interventions specifically targeting gain mutant SOD1, including RNA interference antibodies, show promise, but cure remains elusive. provides comprehensive perspective -associated describes molecular features complex landscape highlighting its importance determining diverse manifestations observed patients emphasizing need for personalized therapeutic strategies.

Language: Английский

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AggreProt: a web server for predicting and engineering aggregation prone regions in proteins

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(W1), P. W159 - W169

Published: May 27, 2024

Recombinant proteins play pivotal roles in numerous applications including industrial biocatalysts or therapeutics. Despite the recent progress computational protein structure prediction, solubility and reduced aggregation propensity remain challenging attributes to design. Identification of aggregation-prone regions is essential for understanding misfolding diseases designing efficient protein-based technologies, as such has a great socio-economic impact. Here, we introduce AggreProt, user-friendly webserver that automatically exploits an ensemble deep neural networks predict (APRs) sequences. Trained on experimentally evaluated hexapeptides, AggreProt compares outperforms state-of-the-art algorithms two independent benchmark datasets. The server provides per-residue profiles along with information solvent accessibility transmembrane within intuitive interface interactive sequence viewers comprehensive analysis. We demonstrate efficacy predicting differential behaviours several use cases, which emphasize its potential guiding engineering strategies towards decreased improved solubility. freely available accessible at https://loschmidt.chemi.muni.cz/aggreprot/.

Language: Английский

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Local structural preferences in shaping tau amyloid polymorphism

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 3, 2024

Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, extent to which intrinsic structural tendencies cores contribute remains uncertain. Using combination experimental approaches, we here identify new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif Repeat 4), as significant contributor polymorphism. Calculation per-residue contributions stability different pathologic structures plays central role in preserving integrity polymorphs. Consistent with this, cryo-EM analysis fibrils formed from synthetic peptide shows sequence adopts alternative closely correspond disease-associated strains. Furthermore, in-cell experiments revealed deletion hampers cellular seeding efficiency aggregates extracted Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal these tauopathies. Together, our results highlight importance propensity core segments determine structure cells, propagating

Language: Английский

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Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Sept. 4, 2024

Language: Английский

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Lipidic folding pathway of α-Synuclein via a toxic oligomer

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to pathogenesis neurodegenerative diseases. The structures filamentous and mature fibrils now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized. We report an atomic-resolution structural characterization toxic aggregation intermediate (I1) on pathway formation lipidic incorporate lipid molecules protofilament surfaces during fibril growth membranes. Super-resolution microscopy reveals tetrameric state, providing insights into early oligomeric assembly. Time resolved nuclear magnetic resonance (NMR) measurements uncover reorganization essential transition I1 L2 fibrils. involves transformation anti-parallel β-strands state β-arc characteristic This reconfiguration occurs conserved kernel shared vast number αS-fibril polymorphs including extracted from Parkinson's Lewy Body Dementia patients. Consistent with reports being defining feature αS intermediates, impacts viability neuroblasts disrupts cell membranes, resulting increased calcium influx. Our results integrate occurrence as salient features oligomers their significant pathway. These have implications development therapies biomarkers.

Language: Английский

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Conserved role of spike S2 domain N-glycosylation across betacoronaviruses

npj Viruses, Journal Year: 2025, Volume and Issue: 3(1)

Published: Jan. 25, 2025

Abstract Besides acting as an immunological shield, the N-glycans of SARS-CoV-2 are also critical for viral life cycle. As S2 subunit spike is highly conserved across betacoronaviruses, we determined functional significance five ‘stem N-glycans’ located in between N1098-N1194. Studies were performed with 31 Asn-to-Gln mutants, betacoronavirus virus-like particles and single-cycle replicons. Deletions stem enhanced S1 shedding from trimeric spike, reduced ACE2 binding abolished syncytia formation. When three or more deleted, expression on cell surface incorporation into virions was both reduced. Viral entry function progressively lost upon deleting N1098 glycan combination additional glycosite modifications. In addition to SARS-CoV-2, SARS-CoV MERS-CoV prevented target cells. These data suggest multiple roles N-glycans, evolutionarily properties these complex carbohydrates human betacoronaviruses.

Language: Английский

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Fluorescent Fingerprint Identification of Protein Structural Changes and Disease-Specific Amyloid Beta Aggregates Based on a Single-Nanozyme Sensor Array

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

The misfolding of amyloid β (Aβ) peptides into an aggregation state is a central hallmark the onset Alzheimer's disease (AD). However, conventional methods are mainly focused on detecting specific Aβ peptide, which makes it difficult to recognize multiple analytes with different topological features and unfolded states at same time. Here, we propose simple universal sensing strategy construct fluorescence sensor array by using single-nanozyme probe combined three fluorescent substrates as recognition units protein structural changes identify between assemblies. In this system, fingerprint-like patterns produced from nonspecific interactions proteins units. As result, can accurately 13 kinds their mixtures ratios. Moreover, discriminate against diverse conformational forms. Most importantly, successfully distinguishes species, even in artificial cerebrospinal fluid samples human serum samples. This work provides attractive reliable for predicting pathologically relevant clinical diagnosis AD.

Language: Английский

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