The Cellular Copper Uptake Mechanism

Copper is a nutrient essential metal, which is involved in many enzymatic and biological processes in the cell. However, insufficient regulation of copper may lead to severe neurological diseases and disorders.

Today’s, it is known that Cu(II) is accumulated in the body through diet to the blood cycle, where human serum albumin (HSA) transfers it to the extra cellular domain of the main copper transporter, CTR1. The first copper binding sites is rich in methionine and histidne residues. In addition, it was suggested that at this site Cu(II) is reduced to Cu(I) in the presence of ascorbate. Segments that are rich with methionine residues, (also called Mets motifs) are found in many of the proteins that bind Cu(I) and are capable of binding Cu(I) and Ag(I) ions with micromolar affinity. Herein, we focus on gaining information on the copper uptake mechanism by the CTR1 protein using several spectroscopic techniques such as EPR, CD, and NMR. We first explored the interaction between the blood carrier protein, HSA, and the extracellular domain of CTR1. We then gained information on the binding of Cu(I) and Ag(I) to a general Mets Motif. We used this information to identify the first Cu(II) and Cu(I) binding sites in CTR1. Finally we explored the Cu(II) reduction mechanism on the CTR1 extracellular domain.

This study presents one step toward a complete understanding of the cellular copper uptake mechanism in the human body.