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bioRxiv · 10.64898/2026.05.26.728006

Phosphoserine clusters as metal ion sensors for protein phase separation

Zakrzewska, E. T.·Mousa, A.·Maurici, N.·Lewicka, D.·Kozminski, W.·Bah, A.·Augustyniak, R.
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Abstract

Phosphorylation is a major regulator of biomolecular condensation, yet it remains unclear whether clustered phosphoserines can directly tune phase behavior via metal-ion coordination. Here, using solution NMR spectroscopy and human heterochromatin protein 1 (HP1) as a model system, we show that stepwise phosphorylation of its N-terminal serine cluster generates a dynamic metal-responsive module that engages Mg{superscript 2}, Ca{superscript 2}, and Mn{superscript 2}, whereas the unmodified protein shows little or no response. Metal coordination lowers the saturation concentration of phosphorylated HP1, reshapes the temperature-dependent stability of its condensates, and modulates the effects of peptide regulators in an ion-specific manner. Our data support a model in which weak, transient metal-mediated contacts enhance intermolecular connectivity between phosphorylated HP1 molecules, promoting reversible condensation alongside canonical electrostatic interactions. These findings establish clustered phosphoserines as sequence-encoded metal-responsive elements that couple post-translational modification to the material properties of biomolecular condensates.

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Zakrzewska, E. T., Mousa, A., Maurici, N., Lewicka, D., Kozminski, W., Bah, A., Augustyniak, R.. 2026-05-29. Phosphoserine clusters as metal ion sensors for protein phase separation. https://doi.org/10.64898/2026.05.26.728006

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