Phosphorylation tunes electrostatically driven protein-RNA interactions
Abstract
Phosphorylation of intrinsically disordered proteins (IDPs) regulates many biomolecular interactions, yet its quantitative effects on binding of highly charged IDPs to nucleic acids remain unclear. Here, we show that multi-site phosphorylation of the disordered arginine/serine-rich (RS) domain of the splicing factor SRSF1 functions as an electrostatic rheostat controlling RNA binding. Using enzymatic phosphorylation, phosphomimetic variants, chemically synthesized phosphopeptides, and single-molecule Förster resonance energy transfer measurements, we identify the RS domain as a strong driver of protein-RNA association. Progressive phosphorylation gradually weakens this interaction, and extensive phosphorylation abolishes detectable RNA binding. Notably, the binding free energy varies linearly with RS domain net charge, independent of whether the charge arises from phosphorylation or acidic phosphomimetic substitutions. Together, our findings establish a quantitative framework for how phosphorylation tunes interactions between charged IDPs and nucleic acids, and rationalize why two acidic amino acid residues are needed to mimic the effect of a single phosphorylation event.
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BibTeX
@article{synakewicz2026phosphorylation,
title = {{Phosphorylation tunes electrostatically driven protein-RNA interactions}},
author = {Marie Synakewicz and Adhvitha Premanand and Héloïse Bürgisser and Sarah Habeler and Lucia R. Franchini and Noémie Kociolek and Mark Nüesch and Antoine Cléry and Daniel Nettels and Frédéric H. -T. Allain and Nina Hartrampf and Benjamin Schuler},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77886-2},
url = {https://www.nature.com/articles/s41467-026-77886-2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Phosphorylation tunes electrostatically driven protein-RNA interactions
AU - Marie Synakewicz
AU - Adhvitha Premanand
AU - Héloïse Bürgisser
AU - Sarah Habeler
AU - Lucia R. Franchini
AU - Noémie Kociolek
AU - Mark Nüesch
AU - Antoine Cléry
AU - Daniel Nettels
AU - Frédéric H. -T. Allain
AU - Nina Hartrampf
AU - Benjamin Schuler
PY - 2026
DA - 2026/10/01
JO - Nature Communications
DO - 10.1038/s41467-026-77886-2
UR - https://www.nature.com/articles/s41467-026-77886-2
AB - Phosphorylation of intrinsically disordered proteins (IDPs) regulates many biomolecular interactions, yet its quantitative effects on binding of highly charged IDPs to nucleic acids remain unclear. Here, we show that multi-site phosphorylation of the disordered arginine/serine-rich (RS) domain of the splicing factor SRSF1 functions as an electrostatic rheostat controlling RNA binding. Using enzymatic phosphorylation, phosphomimetic variants, chemically synthesized phosphopeptides, and single-molecule Förster resonance energy transfer measurements, we identify the RS domain as a strong driver of protein-RNA association. Progressive phosphorylation gradually weakens this interaction, and extensive phosphorylation abolishes detectable RNA binding. Notably, the binding free energy varies linearly with RS domain net charge, independent of whether the charge arises from phosphorylation or acidic phosphomimetic substitutions. Together, our findings establish a quantitative framework for how phosphorylation tunes interactions between charged IDPs and nucleic acids, and rationalize why two acidic amino acid residues are needed to mimic the effect of a single phosphorylation event.
SN - 2041-1723
ER -