Details

Autor(en) / Beteiligte

• Bossak-Ahmad, Karolina
• Mital, Mariusz
• Płonka, Dawid
• Drew, Simon C
• Bal, Wojciech

Titel

Oligopeptides Generated by Neprilysin Degradation of β‑Amyloid Have the Highest Cu(II) Affinity in the Whole Aβ Family

Ist Teil von

• Inorganic chemistry, 2019-01, Vol.58 (1), p.932-943

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The catabolism of β-amyloid (Aβ) is carried out by numerous endopeptidases including neprilysin, which hydrolyzes peptide bonds preceding positions 4, 10, and 12 to yield Aβ4–9 and a minor Aβ12–x species. Alternative processing of the amyloid precursor protein by β-secretase also generates the Aβ11–x species. All these peptides contain a Xxx-Yyy-His sequence, also known as an ATCUN or NTS motif, making them strong chelators of Cu­(II) ions. We synthesized the corresponding peptides, Phe-Arg-His-Asp-Ser-Gly-OH (Aβ4–9), Glu-Val-His-His-Gln-Lys-am (Aβ11–16), Val-His-His-Gln-Lys-am (Aβ12–16), and pGlu-Val-His-His-Gln-Lys-am (pAβ11–16), and investigated their Cu­(II) binding properties using potentiometry, and UV–vis, circular dichroism, and electron paramagnetic resonance spectroscopies. We found that the three peptides with unmodified N-termini formed square-planar Cu­(II) complexes at pH 7.4 with analogous geometries but significantly varied K d values of 6.6 fM (Aβ4–9), 9.5 fM (Aβ12–16), and 1.8 pM (Aβ11–16). Cyclization of the N-terminal Glu11 residue to the pyroglutamate species pAβ11–16 dramatically reduced the affinity (5.8 nM). The Cu­(II) affinities of Aβ4–9 and Aβ12–16 are the highest among the Cu­(II) complexes of Aβ peptides. Using fluorescence spectroscopy, we demonstrated that the Cu­(II) exchange between the Phe-Arg-His and Val-His-His motifs is very slow, on the order of days. These results are discussed in terms of the relevance of Aβ4–9, a major Cu­(II) binding Aβ fragment generated by neprilysin, as a possible Cu­(II) carrier in the brain.