Human serum albumin (HSA) is the
major copper (Cu) carrier
in blood.
The majority of previous studies that have investigated Cu interactions
with HSA have focused primarily on the Cu(II) oxidation state. Yet,
cellular Cu uptake by the human copper transport protein (Ctr1), a
plasma membrane-embedded protein responsible for Cu uptake into cells,
requires Cu(I). Recent in vitro work has determined that reducing
agents, such as the ascorbate present in blood, are sufficient to
reduce the Cu(II)HSA complex to form Cu(I)HSA and that Cu(I) is bound
to HSA with pM affinity. The biological accessibility of Cu(I)HSA
suggests that HSA-bound Cu(I) may be an unappreciated form of Cu cargo
and a key player in extracellular Cu trafficking. To better understand
Cu trafficking by HSA, we sought to investigate the exchange of Cu(I)
from HSA to a model peptide of the Cu-binding ectodomain of Ctr1.
In this study, we used X-ray absorption near-edge spectroscopy to
show that Cu(I) becomes more highly coordinated as increasing amounts
of the Ctr1–14 model peptide are added to a solution
of Cu(I)HSA. Extended X-ray absorption fine structure (EXAFS) spectroscopy
was used to further characterize the interaction of Cu(I)HSA with
Ctr1–14 by determining the ligands coordinating
Cu(I) and their bond lengths. The EXAFS data support that some Cu(I)
likely undergoes complete transfer from HSA to Ctr1–14. This finding of HSA interacting with and releasing Cu(I) to an
ectodomain model peptide of Ctr1 suggests a mechanism by which HSA
delivers Cu(I) to cells under physiological conditions.
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