Molecular Insights into Human Serum Albumin as a Receptor of Amyloid-beta in the Extracellular Region

Abstract

Regulation of amyloid-beta (A beta) aggregation by metal ions and proteins is essential for understanding the pathology of Alzheimer's disease (AD). Human serum albumin (HSA), a regulator of metal and protein transportation, can modulate metal-A beta interactions and A beta aggregation in human fluid; however, the molecular mechanisms for such activities remain unclear. Herein, we report the molecular-level complexation between Zn(II), Cu(II), A beta, and HSA, which is able to alter the aggregation and cytotoxicity of A beta peptides and induce their cellular transportation. In addition, a single A beta monomer-bound HSA is observed with the structural change of A beta from a random coil to an alpha-helix. Small-angle X-ray scattering (SAXS) studies indicate that A beta-HSA complexation causes no structural variation of HSA in solution. Conversely, ion mobility mass spectrometry (IM-MS) results present that A beta prevents the shrinkage of the V-shaped groove of HSA in the gas phase. Consequently, for the first time, HSA is demonstrated to predominantly capture a single A beta monomer at the groove using the phase transfer of a protein heterodimer from solution to the gas phase. Moreover, HSA sequesters Zn(II) and Cu(II) from A beta while maintaining A beta-HSA interaction. Therefore, HSA is capable of controlling metal-free and metal-bound A beta aggregation and aiding the cellular transportation of A beta via A beta-HSA complexation. The overall results and observations regarding HSA, A beta, and metal ions advance our knowledge of how protein-protein interactions associated with A beta and metal ions could be linked to AD pathogenesis.