Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.
Adv Sci (Weinh)
; 10(25): e2207742, 2023 09.
Article
en En
| MEDLINE
| ID: mdl-37386790
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 ß-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 ß-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 ß-sheet fibrils in FUS-RNA condensates, maintaining functional liquid-like behavior without ageing.
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Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas de Unión al ARN
Idioma:
En
Revista:
Adv Sci (Weinh)
Año:
2023
Tipo del documento:
Article
País de afiliación:
España