Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates

Area of Science:

• Biophysics
• Molecular Biology
• Biochemistry

Background:

• Biomolecular condensates exhibit viscoelastic properties.
• The prion-like low-complexity domain (LCD) of hnRNP A1 forms such condensates.
• Understanding sequence-encoded and age-dependent viscoelasticity is crucial.

Purpose of the Study:

• Investigate sequence determinants of condensate viscoelasticity.
• Characterize age-dependent transitions in hnRNP A1 LCD condensates.
• Explore the role of sequence grammar in controlling condensate phase behavior.

Main Methods:

• Formation and characterization of condensates from hnRNP A1 LCD and variants.
• Rheological measurements to determine viscoelastic moduli.
• Application of Rouse-Zimm polymer dynamics model.
• Analysis of sequence-specific interactions and aging dynamics.

Main Results:

• Condensates are metastable Maxwell fluids, transitioning to Kelvin-Voigt solids upon aging.
• Aromatic inter-sticker interactions dictate sequence-specific viscoelastic properties.
• Aging is sequence-dependent, driven by weakened metastability of viscous phases.
• Disorder-to-order transitions and beta-sheet formation accompany aging.

Conclusions:

• Sequence grammar in prion-like LCDs controls condensate metastability.
• Evolved sequences prevent fluid-to-solid conversion on functional timescales.
• Condensate aging dynamics are governed by sequence-encoded interactions and phase stability.