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

• Published in: Advanced science Vol. 10; no. 25; pp. e2207742 - n/a
• Main Authors: Blazquez, Samuel, Sanchez‐Burgos, Ignacio, Ramirez, Jorge, Higginbotham, Tim, Conde, Maria M., Collepardo‐Guevara, Rosana, Tejedor, Andres R., Espinosa, Jorge R.
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.09.2023; John Wiley and Sons Inc; Wiley
• Subjects: Aging; Amino acids; Amyotrophic lateral sclerosis; computer simulations; condensate ageing; Energy; liquid‐liquid phase separation; Mutation; Peptides; Phase transitions; Physiology; protein aggregation; Proteins; Simulation; Viscosity; β‐sheet folding; β-sheet folding; computer simulations; condensate ageing; liquid-liquid phase separation; protein aggregation
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202207742

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. Biomolecular condensates importantly contribute to the spatiotemporal organization of the cell. However, condensates can age over time transitioning into gel‐like pathological aggregates. Here, by combining atomistic and coarse‐grained simulations, the authors investigate how the concentration and location of low‐complexity aromatic‐rich kinked segments—susceptible of developing inter‐protein β‐sheet transitions—control the ageing rate of protein condensates. Strikingly, the authors find how just the reposition of these segments across the protein sequence can severely regulate condensate ageing.