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Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.

ABSTRACT: Maturation of functional liquid-like biomolecular condensates into solid-like aggregates has been linked to the onset of several neurodegenerative disorders. Low-complexity aromatic-rich kinked segments (LARKS) contained in numerous RNA-binding proteins can promote aggregation by forming inter-protein β-sheet fibrils that accumulate over time and ultimately drive the liquid-to-solid transition of the condensates. Here, atomistic molecular dynamics simulations are combined with sequence-dependent coarse-grained models of various resolutions to investigate the role of LARKS abundance and position within the amino acid sequence in the maturation of condensates. Remarkably, proteins with tail-located LARKS display much higher viscosity over time than those in which the LARKS are placed toward the center. Yet, at very long timescales, proteins with a single LARKS-independently of its location-can still relax and form high viscous liquid condensates. However, phase-separated condensates of proteins containing two or more LARKS become kinetically trapped due to the formation of percolated β-sheet networks that display gel-like behavior. Furthermore, as a work case example, they demonstrate how shifting the location of the LARKS-containing low-complexity domain of FUS protein toward its center effectively precludes the accumulation of β-sheet fibrils in FUS-RNA condensates, maintaining functional liquid-like behavior without ageing.

SUBMITTER: Blazquez S

PROVIDER: S-EPMC10477902 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.

Blazquez Samuel S Sanchez-Burgos Ignacio I Ramirez Jorge J Higginbotham Tim T Conde Maria M MM Collepardo-Guevara Rosana R Tejedor Andres R AR Espinosa Jorge R JR

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230629 25

Maturation of functional liquid-like biomolecular condensates into solid-like aggregates has been linked to the onset of several neurodegenerative disorders. Low-complexity aromatic-rich kinked segments (LARKS) contained in numerous RNA-binding proteins can promote aggregation by forming inter-protein β-sheet fibrils that accumulate over time and ultimately drive the liquid-to-solid transition of the condensates. Here, atomistic molecular dynamics simulations are combined with sequence-dependent ...[more]

PMID: 37386790

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Dataset Information

Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.

Publications

Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.

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