Phosphate-Rich Biomimetic Peptides Shed Light on High-Affinity Hyperphosphorylated Uranyl Binding Sites in Phosphoproteins.

Some phosphoproteins such as osteopontin (OPN) have been identified as high-affinity uranyl targets. However, the binding sites required for interaction with uranyl and therefore involved in its toxicity have not been identified in the whole protein. The biomimetic approach proposed here aimed to decipher the nature of these sites and should help to understand the role of the multiple phosphorylations in UO binding. Two hyperphosphorylated cyclic peptides, pS and pS containing up to four phosphoserine (pSer) residues over the ten amino acids present in the sequences, were synthesized with all reactions performed in the solid phase, including post-phosphorylation. These β-sheet-structured peptides present four coordinating residues from four amino acid side chains pointing to the metal ion, either three pSer and one glutamate in pS or four pSer in pS . Significantly, increasing the number of pSer residues up to four in the cyclodecapeptide scaffolds produced molecules with an affinity constant for UO that is as large as that reported for osteopontin at physiological pH. The phosphate-rich pS can thus be considered a relevant model of UO coordination in this intrinsically disordered protein, which wraps around the metal ion to gather four phosphate groups in the UO coordination sphere. These model hyperphosphorylated peptides are highly selective for UO with respect to endogenous Ca , which makes them good starting structures for selective UO complexation.