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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.
Sprache
Englisch
Identifikatoren
ISSN: 0020-1669
eISSN: 1520-510X
DOI: 10.1021/acs.inorgchem.8b03051
Titel-ID: cdi_proquest_miscellaneous_2160149150
Format
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