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The role of N-terminal acetylation on biomolecular condensation

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G. Oliveira, Carolina, Silva, Mayra T. S., Kava, Emanuel, Agarwal, Tanushree, Cereghetti, Gea, F. Vicente, Eduardo, Knowles, Tuomas P. J., Costa-Filho, Antonio J., Mendes, Luis F. S.·2026·Communications Chemistry
DOI 10.1038/s42004-026-01975-yPMC PMC13427742

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Abstract

Abstract N-terminal acetylation (Nt-acetylation) is one of the most prevalent co-translational modifications in eukaryotes, affecting nearly 80% of the human proteome. Despite its ubiquity, the potential impact of this phenomenon on biomolecular condensation has been largely overlooked. Here, we uncover how this chemically subtle modification can exert broad and multifaceted control over phase behaviour, using Grh1, a Golgi-associated protein involved in stress-induced secretion in yeast, as a model system. We show that Nt-acetylation increases the saturation concentration for condensation, reduces droplet size and number, dampens pH sensitivity, weakens electrostatic contributions, and suppresses water dipolar relaxation within condensates, indicating reduced internal hydration and environmental responsiveness. These effects are accompanied by acetylation-dependent dimerisation and local structural changes, including a concentration-dependent gain in α-helicity. Remarkably, co- condensation assays reveal that acetylated and non-acetylated forms of the same protein are only partially miscible, giving rise to core-shell architectures driven by differences in interfacial tension. Together, our findings highlight Nt-acetylation as a potent, generalizable regulator of condensate material properties, linking primary sequence chemistry to mesoscale organisation. Given its evolutionary conservation and prevalence across eukaryotic proteomes, Nt-acetylation may represent a widespread mechanism for modulating protein condensation in health and disease.

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Metadata

Authors
G. Oliveira, C., Silva, M. T. S., Kava, E., Agarwal, T., Cereghetti, G., F. Vicente, E., Knowles, T. P. J., Costa-Filho, A. J., & Mendes, L. F. S.
Affiliations
  • Universidade de São Paulo (BR)
  • University of Cambridge (GB)
Corresponding author
Costa-Filho, Antonio J.
ORCID
Venue
Communications Chemistry
Publisher
Springer Science and Business Media LLC
Published
2026-04-11
Volume
9
Issue
1
ISSN
2399-3669 (ISSN-L)
DOI
10.1038/s42004-026-01975-y
PMC
PMC13427742
OpenAlex
W4413612122
Cited by
2
References
1
Citations by year
2026: 2
FWCI
4.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Chemistry (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
N-terminal acetylation, biomolecular condensation, phase separation, Golgi-associated proteins, co-translational modification, protein dimerization, alpha-helix content, interfacial tension, droplet size, hydration, pH sensitivity, electrostatic interactions, yeast

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