Structure and Affinity of Cu(I) Bound to Human Serum Albumin

Area of Science:

• Biochemistry
• Metalloprotein Chemistry
• Neuroscience

Background:

• Human serum albumin (HSA) is the primary copper (Cu) carrier in blood and cerebrospinal fluid.
• Previous research focused on Cu(II)-HSA interactions, assuming Cu(I) binding was negligible.
• HSA's role in Cu(I) binding and its coordination chemistry remained largely uninvestigated.

Purpose of the Study:

• To characterize the affinity of HSA for Cu(I).
• To determine the coordination structure of Cu(I) bound to HSA.
• To assess the significance of Cu(I)-HSA interactions in biological systems.

Main Methods:

• Solution competition experiments to determine apparent affinity.
• X-ray absorption spectroscopy (XAS) to elucidate coordination structure.
• In silico modeling to complement experimental findings.

Main Results:

• HSA exhibits a high apparent conditional affinity for Cu(I) (K_Cu(I):HSA = 10^14.0) at pH 7.4.
• Cu(I) binds to HSA in a digonal coordination, similar to histidine coordination in amyloid beta and prion proteins.
• This binding occurs despite the common assumption of Cu(II) as the primary species interacting with HSA.

Conclusions:

• HSA binds Cu(I) with a surprisingly high affinity, suggesting a significant, overlooked role in copper transport.
• The characterized Cu(I) coordination structure provides insights into metalloprotein interactions.
• Cu(I)-HSA interactions warrant further investigation for their implications in human physiology and disease.