Agents mobilizing Cu(II) from the inert ATCUN complex need both high affinity and a specific chelating structure

ATCUN motifs at the N-termini of defined and putative Cu(II) handling proteins provide tight Cu(II) ion binding and prevent the unwanted redox activity of the ion. On the other hand, the Cu(II)-ATCUN complexes exhibit slow or very slow (hours to days) kinetics of Cu(II) exchange with other, ATCUN and non-ATCUN chelators. We chose a number of small molecules involved in copper physiology, bearing different Cu(II) binding groups and screened their ability to accelerate the Cu(II) ion transfer from Aβ_4-16, an ATCUN β-amyloid model peptide to EDTA serving as a thermodynamic Cu(II) sink representing copper receptors and transporters. The transfer was enhanced specifically by histidine and His-Leu dipeptide, sharing a two-coordinate amine/imidazole structural motif assisted by an oxygen donor and providing sufficient thermodynamic stability of Cu(II) ion binding. This result is consistent with the reaction model including a structurally specific ternary intermediate, and paves a way for further investigations of physiological copper transfers.