Journal
INORGANIC CHEMISTRY
Volume 58, Issue 1, Pages 932-943Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.8b03051
Keywords
-
Categories
Funding
- National Science Centre of Poland [2014/15/B/ST5/05229]
- Centre for Preclinical Research and Technology (CePT)
- European Regional Development Fund
- faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne
- Innovative Economy, The National Cohesion Strategy of Poland
Ask authors/readers for more resources
The catabolism of beta-amyloid (A beta) is carried out by numerous endopeptidases including neprilysin, which hydrolyzes peptide bonds preceding positions 4, 10, and 12 to yield A beta(4-9) and a minor A beta(12-x) species. Alternative processing of the amyloid precursor protein by beta-secretase also generates the A beta(11-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 (A beta(4-9)), Glu-Val-His-His-Gln-Lys-am (A beta(11-16)), Val-His-His-Gln-Lys-am (A beta(12-16)), and pG1u-Val-His-His-Gln-Lysam (pA beta(11-16)), 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 (A beta(4-9)), 9.5 fM (A beta(12-16)), and 1.8 pM (A beta(11-16)). Cyclization of the N-terminal Glull residue to the pyroglutamate species pA beta(11-16) dramatically reduced the affinity (5.8 nM). The Cu(II) affinities of A beta(4-9) and A beta(12-16) are the highest among the Cu(II) complexes of A beta 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 A beta(4-9), a major Cu(II) binding A beta fragment generated by neprilysin, as a possible Cu(II) carrier in the brain.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available