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bioRxiv · 10.1101/2024.10.18.617420

Global comparative structural analysis of responses to protein phosphorylation

Correa Marrero, M.·Mello, V. H.·Sartori, P.·Beltrao, P.
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Abstract

Post-translational modifications (PTMs), particularly protein phosphorylation, are key regulators of cellular processes, impacting numerous aspects of protein activity. Despite widespread phosphorylation of eukaryotic proteomes, the function of most phosphosites remains unknown. Elucidating the structural mechanisms underlying phosphorylation is crucial for understanding its regulatory roles. Here, we conducted a comparative structural analysis of phosphorylated and non-phosphorylated proteins taken from the Protein Data Bank (PDB). Our study systematically evaluates how phosphorylation affects backbone conformation, protein dynamics, and mechanical strain. We found that phosphorylation commonly induces small, stabilizing conformational changes through conformational selection and frequently modulates local residue fluctuations, influencing overall protein motion. Notably, a small but significant subset of phosphosites shows mechanical coupling with functional sites, aligning with the domino model of allosteric signal transduction. This work provides a foundation for studying phosphorylation and other PTMs in their structural context, which will guide the rational design of synthetic phosphosites and enable the engineering of PTM-driven regulatory circuits in synthetic biology.

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Correa Marrero, M., Mello, V. H., Sartori, P., Beltrao, P.. 2024-10-20. Global comparative structural analysis of responses to protein phosphorylation. https://doi.org/10.1101/2024.10.18.617420

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