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

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author Hugh I. Kim
journal J. Am. Chem. Soc., Just Accepted Manuscript(DOI: 10.1021/jacs.7b08584)


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Tae Su Choi(Post doc.)

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 to 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 HSA–Aβ 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.



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