Cyclic Phosphopeptides to Rationalize the Role of Phosphoamino Acids in Uranyl Binding to Biological Targets.
The specific molecular interactions responsible for uranium toxicity are not yet understood. The uranyl binding sites in high-affinity target proteins have not been identified yet and the involvement of phosphoamino acids is still an important question. Short cyclic peptide sequences, with three glutamic acids and one phosphoamino acid, are used as simple models to mimic metal binding sites in phosphoproteins and to help understand the mechanisms involved in uranium toxicity. A combination of peptide design and synthesis, analytical chemistry, extended X-ray absorption fine structure (EXAFS) spectroscopy, and DFT calculations demonstrates the involvement of the phosphate group in the uranyl coordination sphere together with the three carboxylates of the glutamate moieties. The affinity constants measured with a reliable analytical competitive approach at physiological pH are significantly enhanced owing to the presence of the phosphorous moiety. These findings corroborate the importance of phosphoamino acids in uranyl binding in proteins and the relevance of considering phosphoproteins as potential uranyl targets in vivo.
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Matthieu
M
Starck
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Fanny A
FA
Laporte
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Stephane
S
Oros
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Nathalie
N
Sisommay
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Vicky
V
Gathu
Synchrotron SOLEIL, L'orme des Merisiers, Saint-Aubin, 91192, Gif-sur-Yvette, France.
Pier Lorenzo
PL
Solari
Institut de Chimie de Nice, UMR7272, Université Côte d'Azur, 06108, Nice, France.
Gaëlle
G
Creff
Institut de Physique Nucléaire d'Orsay, CNRS-IN2P3, Univ. Paris-Sud, Université Paris-Saclay, France.
Jérôme
J
Roques
Institut de Chimie de Nice, UMR7272, Université Côte d'Azur, 06108, Nice, France.
Christophe
C
Den Auwer
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Colette
C
Lebrun
INAC/SyMMES, UMR5819, Université Grenoble Alpes, CEA, CNRS, 38000, Grenoble, France.
Pascale
P
Delangle
D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D019606:Phosphoamino Acids / Q000737:chemistry*; D010748:Phosphopeptides / Q000737:chemistry*; D014501:Uranium / Q000737:chemistry*; D056928:X-Ray Absorption Spectroscopy
D002264:Carboxylic Acids; D010456:Peptides, Cyclic; D019606:Phosphoamino Acids; D010748:Phosphopeptides; D014501:Uranium
affinity; bioinorganic chemistry; peptides; phosphates; uranium