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Zinc ions trigger the prion protein liquid-liquid phase separation
Mariana Juliani do Amaral1, Letícia Soares de Oliveira1, Yraima Cordeiro1
1Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
Biochemical and Biophysical Research Communications
|February 21, 2025
Summary
Zinc ions (Zn2+) induce liquid-like prion protein (PrP) condensates, differing from copper ions. This metal-induced phase separation, dependent on PrP's N-terminal domain, impacts protein aggregation and may regulate PrP's role in metal uptake.
Area of Science:
- Biochemistry
- Neuroscience
- Cell Biology
Background:
- Prion diseases involve prion protein (PrP) misfolding into pathogenic aggregates (PrPSc).
- Biomolecular condensates of PrP can mature into pathological aggregates, influenced by nucleic acids and oxidative stress.
- Copper ions (Cu2+) induce liquid-like PrP condensates, affecting PrP behavior in cells.
Purpose of the Study:
- To investigate if zinc ions (Zn2+) modulate PrP phase separation differently than copper ions.
- To explore the role of the N-terminal domain in metal-induced PrP condensation.
- To compare the molecular properties of Zn2+- and Cu2+-induced PrP condensates.
Main Methods:
- Recombinant prion protein (PrP) phase separation assays with Zn2+ under controlled buffer conditions.
- Fluorescence Recovery After Photobleaching (FRAP) to assess condensate dynamics.
- Thioflavin T aggregation kinetics to monitor PrP misfolding and aggregation.
Main Results:
- Recombinant PrP undergoes Zn2+-induced phase separation, forming liquid-like condensates.
- Zn2+- and Cu2+-induced PrP condensation depend on the N-terminal domain (residues 23-90).
- PrP:Zn2+ condensates show faster FRAP recovery than PrP:Cu2+ condensates, indicating distinct dynamics.
- Cu2+ strongly inhibits PrP misfolding, while Zn2+ causes a milder delay in aggregation.
Conclusions:
- Zn2+ induces distinct PrP phase separation dynamics compared to Cu2+.
- PrP condensation is regulated by the N-terminal domain and influenced by specific metal ions.
- Findings support roles for PrP in metal sequestering and uptake, potentially via biomolecular condensation.
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