Model Peptide Studies Reveal a Mixed Histidine-Methionine
Cu(I) Binding Site at the N‑Terminus of Human Copper Transporter
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Abstract
Copper
is a vital metal cofactor in enzymes that are essential to myriad
biological processes. Cellular acquisition of copper is primarily
accomplished through the Ctr family of plasma membrane copper transport
proteins. Model peptide studies indicate that the human Ctr1 N-terminus
binds to Cu(II) with high affinity through an amino terminal Cu(II),
Ni(II) (ATCUN) binding site. Unlike typical ATCUN-type peptides, the
Ctr1 peptide facilitates the ascorbate-dependent reduction of Cu(II)
bound in its ATCUN site by virtue of an adjacent HH (<i>bis</i>-His) sequence in the peptide. It is likely that the Cu(I) coordination
environment influences the redox behavior of Cu bound to this peptide;
however, the identity and coordination geometry of the Cu(I) site
has not been elucidated from previous work. Here, we show data from
NMR, XAS, and structural modeling that sheds light on the identity
of the Cu(I) binding site of a Ctr1 model peptide. The Cu(I) site
includes the same <i>bis</i>-His site identified in previous
work to facilitate ascorbate-dependent Cu(II) reduction. The data
presented here are consistent with a rational mechanism by which Ctr1
provides coordination environments that facilitate Cu(II) reduction
prior to Cu(I) transport