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Crowding-Induced Liquid-Liquid Phase Separation in the ATP-Binding ACC1-13K8 Peptide Leads to a Distinct Amyloid
Robert Dec1, Wojciech Dzwolak2, Roland Winter1
1Physical Chemistry I - Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn Street 4a, 44227 Dortmund, Germany.
Biomacromolecules
|January 27, 2026
Summary
Macromolecular crowding, like polyethylene glycol (PEG), can induce liquid-liquid phase separation (LLPS) in peptides, promoting amyloid fibril formation. Different crowding agents impact protein aggregation pathways and the resulting amyloid structures.
Area of Science:
- Biochemistry
- Biophysics
- Cell Biology
Background:
- Liquid-liquid phase separation (LLPS) is crucial for cellular organization and implicated in protein misfolding diseases.
- LLPS can precede a liquid-solid phase transition (LSPT) leading to amyloid aggregates.
- Chimeric ACC1-13Kn peptides serve as models for studying coupled LLPS/LSPT.
Purpose of the Study:
- To investigate how macromolecular crowding affects the aggregation pathway of ACC1-13K8 peptides triggered by ATP.
- To understand the role of polyethylene glycol (PEG) in inducing LLPS and subsequent fibril formation.
- To compare the effects of different crowding agents on protein aggregation.
Main Methods:
- Utilized chimeric ACC1-13K8 peptides and ATP to model coupled LLPS/LSPT.
- Introduced various macromolecular crowding agents: polyethylene glycol (PEG), Dextran, Ficoll, and serum albumin.
- Analyzed the impact of crowding on LLPS, fibril formation kinetics, and fibril characteristics (infrared, morphology, stability).
Main Results:
- Concentrated PEG induced LLPS and subsequent fibril formation, unlike shorter peptides.
- PEG's effect contrasted with Dextran/Ficoll (accelerated aggregation without LLPS) and serum albumin (prolonged nucleation).
- PEG-induced crowding led to distinct ACC1-13K8-ATP fibrils with altered characteristics and stability.
- Fibrillization rate in PEG-crowded conditions was limited by diffusion and conformational dynamics.
Conclusions:
- Macromolecular crowding can select between kinetically and thermodynamically favored amyloid polymorphs.
- The chemical nature of crowding agents is critical in modulating protein aggregation.
- Findings provide insights into LLPS-dependent protein misfolding and amyloid formation mechanisms.
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