Agents mobilizing Cu(II) from the inert ATCUN complex need both high affinity and a specific chelating structure
Paulina Szczerba1, Ewelina Stefaniak2, Dawid Płonka1
1Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Journal of Inorganic Biochemistry
|June 13, 2026
Summary
Copper-binding ATCUN motifs tightly bind Cu(II) but exchange slowly. Histidine and His-Leu dipeptide accelerate copper ion transfer from Aβ4-16, aiding copper transport research.
Area of Science:
- Biochemistry
- Metalloprotein Chemistry
- Neuroscience
Background:
- ATCUN motifs in proteins bind Cu(II) ions, preventing redox activity.
- Cu(II)-ATCUN complexes exhibit slow copper ion exchange kinetics.
- Understanding copper ion transfer is crucial for cellular copper homeostasis.
Purpose of the Study:
- To investigate small molecules that can accelerate Cu(II) ion transfer from an Aβ peptide model.
- To identify specific structural features that facilitate copper ion exchange.
- To explore mechanisms of physiological copper transfer.
Main Methods:
- Screening small molecules for their ability to accelerate Cu(II) transfer from Aβ4-16 peptide.
- Utilizing EDTA as a thermodynamic sink for Cu(II) ions.
- Analyzing copper transfer kinetics based on molecular structure.
Main Results:
- Histidine and His-Leu dipeptide specifically enhanced Cu(II) ion transfer from Aβ4-16.
- A two-coordinate amine/imidazole structural motif, with an oxygen donor, was key for acceleration.
- The findings support a reaction model involving a specific ternary intermediate.
Conclusions:
- Specific small molecules can overcome the slow kinetics of Cu(II)-ATCUN complexes.
- Histidine-containing dipeptides are effective in promoting physiological copper transfer.
- This research provides a foundation for studying copper transport mechanisms in biological systems.
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