Copper drives prion protein phase separation and modulates aggregation

Science Advances, Journal Year: 2023, Volume and Issue: 9(44)

Published: Nov. 3, 2023

Prion diseases are characterized by prion protein (PrP) transmissible aggregation and neurodegeneration, which has been linked to oxidative stress. The physiological function of PrP seems related sequestering redox-active Cu 2+ , dyshomeostasis is observed in disease brain. It unclear whether contributes aggregation, recently shown be mediated condensation. This study indicates that promotes condensation live cells at the cell surface vitro through copartitioning. Molecularly, inhibited β-structure hydrophobic residues exposure. Oxidation, induced H 2 O triggered liquid-to-solid transition PrP:Cu condensates promoted amyloid-like aggregation. In cells, overexpression C initially protected against cytotoxicity but led upon extended copper Our data suggest as a buffer for prevents toxicity can into prolonged

Language: Английский

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Self-assembly coupled to liquid-liquid phase separation

PLoS Computational Biology, Journal Year: 2023, Volume and Issue: 19(5), P. e1010652 - e1010652

Published: May 15, 2023

Liquid condensate droplets with distinct compositions of proteins and nucleic acids are widespread in biological cells. While it is known that such droplets, or compartments, can regulate irreversible protein aggregation, their effect on reversible self-assembly remains largely unexplored. In this article, we use kinetic theory solution thermodynamics to investigate the liquid-liquid phase separation structures well-defined sizes architectures. We find that, when assembling subunits preferentially partition into liquid robustness against traps maximum achievable assembly rates be significantly increased. particular, both range conditions leading productive corresponding increase by orders magnitude. analyze rate equation predictions using simple scaling estimates identify effects as a function relevant control parameters. These results may elucidate processes underlie normal cellular functions pathogenesis, suggest strategies for designing efficient bottom-up nanomaterials applications.

Language: Английский

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Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 75, P. 102333 - 102333

Published: May 31, 2023

Language: Английский

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α-Synuclein liquid condensates fuel fibrillar α-synuclein growth

Science Advances, Journal Year: 2023, Volume and Issue: 9(33)

Published: Aug. 16, 2023

α-Synuclein (α-Syn) aggregation into fibrils with prion-like features is intimately associated Lewy pathology and various synucleinopathies. Emerging studies suggest that α-Syn could form liquid condensates through phase separation. The role of these in disease remains elusive the interplay between unexplored, possibly due to difficulties triggering formation cells. To address this gap, we developed an assay allowing controlled assembly/disassembly cells studied them upon exposure preformed fibrillar polymorphs. Fibrils triggered evolution solid-like structures displaying growing needle-like extensions exhibiting pathological amyloid hallmarks. No such changes were elicited on did not undergo We, therefore, propose a model where within fuels exogenous seeds growth, thus speeding up propagation pathogenic aggregates.

Language: Английский

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Sequence-Dependent Conformational Transitions of Disordered Proteins During Condensation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 12, 2024

Intrinsically disordered proteins (IDPs) can form biomolecular condensates through phase separation. It is recognized that the conformation of IDPs in dense and dilute phases as well at interfaces critically impact resulting properties associated with their functionality. However, a comprehensive understanding conformational transitions during condensation remains elusive. In this study, we employ coarse-grained polyampholyte model, comprising an equal number oppositely charged residues-glutamic acid lysine-whereby conformations behavior be readily tuned by altering protein sequence. By manipulating sequence patterns from perfectly alternating to block-like, obtain chains ideal-like semi-compact structures phase, while chain approximately ideal chain, irrespective performing simulations different concentrations, find assemble small oligomeric clusters accompanied gradual swelling individual chains. We further demonstrate these findings are applicable several naturally occurring involved formation biological condensates. Concurrently, delve deeper into within condensate, revealing interface show strong dependence, but remain more collapsed than those bulk-like phase. This study addresses critical gaps our knowledge IDP function

Language: Английский

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