Regulation of amyloid-β
(Aβ) 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–Aβ interactions
and Aβ 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), Aβ, and HSA, which is able
to alter the aggregation and cytotoxicity of Aβ peptides and
induce their cellular transportation. In addition, a single Aβ
monomer-bound HSA is observed with the structural change of Aβ
from a random coil to an α-helix. Small-angle X-ray scattering
(SAXS) studies indicate that Aβ–HSA complexation causes
no structural variation of HSA in solution. Conversely, ion mobility
mass spectrometry (IM-MS) results present that Aβ 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 Aβ 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 Aβ while maintaining Aβ–HSA
interaction. Therefore, HSA is capable of controlling metal-free and
metal-bound Aβ aggregation and aiding the cellular transportation
of Aβ via Aβ–HSA complexation. The overall results
and observations regarding HSA, Aβ, and metal ions advance our
knowledge of how protein–protein interactions associated with
Aβ and metal ions could be linked to AD pathogenesis
