Controlling interfacial protein adsorption, desorption and aggregation in biomolecular condensates

Brent S. Visser, Merlijn H. I. van Haren, Wojciech P. Lipiński, Kirsten A. van Leijenhorst-Groener, Mireille M.A.E. Claessens, Marcos V. A. Queirós, Carlos H. I. Ramos, Jorine Eeftens and Evan Spruijt ()
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Brent S. Visser: Radboud University, Institute for Molecules and Materials
Merlijn H. I. van Haren: Radboud University, Institute for Molecules and Materials
Wojciech P. Lipiński: Radboud University, Institute for Molecules and Materials
Kirsten A. van Leijenhorst-Groener: University of Twente, Nanobiophysics, Faculty of Science and Technology, MESA+ Institute for Nanotechnology and Technical Medical Centre
Mireille M.A.E. Claessens: University of Twente, Nanobiophysics, Faculty of Science and Technology, MESA+ Institute for Nanotechnology and Technical Medical Centre
Marcos V. A. Queirós: Radboud University, Institute for Molecules and Materials
Carlos H. I. Ramos: Universidade Estadual de Campinas (UNICAMP), Instituto de Química
Jorine Eeftens: Radboud University, Radboud Institute for Molecular Life Sciences
Evan Spruijt: Radboud University, Institute for Molecules and Materials

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Aggregation of amyloidogenic proteins is linked to age-related diseases. The presence of interfaces can affect their aggregation mechanism, often speeding up aggregation. α-Synuclein (αSyn) can adsorb to biomolecular condensates, leading to heterogenous nucleation and faster aggregation. Understanding the mechanism underlying localization of amyloidogenic proteins at condensate interfaces is crucial for developing strategies to prevent or reverse their binding. We show that αSyn localization to the surface of peptide-based heterotypic condensates is an adsorption process governed by the protein’s condensate-amphiphilic nature, and the condensate surface charge. Adsorption occurs reversibly in multiple layers and plateaus at micromolar concentrations. Based on these findings, we rationally design three strategies to modulate αSyn accumulation: (i) addition of biomolecules that decrease the condensate ζ-potential, such as NTPs and RNA, (ii) competitive adsorption of proteins targeting the condensate interface, such as G3BP1, DDX4-YFP, EGFP-NPM1, Hsp70, Hsc70, and (iii) preferential adsorption of αSyn to membranes. Removing αSyn from the condensate interface slows aggregation, highlighting potential cellular control over protein adsorption and implications for therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-65030-5

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