Effect of Cu2+ and Zn2+ ions on human serum albumin interaction with plasma unsaturated fatty acids

Abstract

Human serum albumin (HSA) serves as a depot and carrier of multiple unrelated ligands including several participants of the pathogenesis of Alzheimer's disease (AD), such as amyloid β peptide (Aβ), Zn²⁺/Cu²⁺ ions, docosahexaenoic (DHA), linoleic (LA), and oleic (OA) acids. To explore the interplay between HSA interaction with Zn²⁺/Cu²⁺ and the plasma unsaturated fatty acids (DHA, LA, OA, and arachidonic acid (ArA)), we have studied the metal dependence of the fatty acid (FA) binding capacity of HSA (n_max) and structural consequences of the HSA-FA interactions. HSA loading with Zn²⁺ decreases n_max value by 0.3-1.5, while its saturation with Cu²⁺ causes the FA-dependent n_max changes by up to 0.9. The Cu²⁺-induced decline in n_max value for DHA is due to conformational rearrangements in HSA molecule. In other cases, the changes in n_max are attributed to steric hindarance/facilitation of the HSA-FA interaction because of the protein multimerization/monomerization, as confirmed by chemical crosslinking. The surface hydrophobicity of HSA is Cu²⁺-, Zn²⁺-, and FA-dependent and decreases upon the FA binding, according to bis-ANS fluorescence data. Overall, Zn²⁺ or Cu²⁺ binding selectively affect HSA interaction with the FAs studied, in part due to changes in quaternary structure of the protein.

Keywords: Copper; Fatty acid; Protein-ligand interaction; Protein-lipid interaction; Serum albumin; Zinc.