Intrinsically disordered regions of proteins, which lack unique tertiary structure under physiological conditions, are enriched in phosphorylation sites and in significant local bias toward the polyproline II conformation. The overrepresented coincidence of this posttranslational regulatory signal and local conformational bias within unstructured regions raises a question: can phosphorylation serve to manipulate the conformational preferences of a disordered protein? In this study, we use time-resolved fluorescence resonance energy transfer and a, to our knowledge, novel data analysis method to directly measure the end-to-end distance distribution of a phosphorylatable peptide derived from the human microtubule associated protein tau. Our results show that phosphorylation at threonine or serine extends the end-to-end distance and increases the effective persistence length of the tested model peptides. Unexpectedly, the extension is independent of salt concentration, suggestive of a nonelectrostatic origin. The phosphorylation extension and stiffening effect provides a peptide-scale physical interpretation for the posttranslational regulation of the highly abundant protein-protein interactions found in disordered proteins, as well as a potential insight into the regulatory mechanism of the tau protein's microtubule binding activity.
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