Aβ_5–x Peptides: N-Terminal Truncation Yields Tunable Cu(II) Complexes

Abstract

The Aβ 5– x peptides ( x = 38, 40, 42) are minor Aβ species in normal brains but elevated upon the application of inhibitors of Aβ processing enzymes. They are interesting from the point of view of coordination chemistry for the presence of an Arg-His metal binding sequence at their N-terminus capable of forming a 3-nitrogen (3N) three-coordinate chelate system. Similar sequences in other bioactive peptides were shown to bind Cu(II) ions in biological systems. Therefore, we investigated Cu(II) complex formation and reactivity of a series of truncated Aβ 5– x peptide models comprising the metal binding site: Aβ 5–9 , Aβ 5–12 , Aβ 5–12 Y10F, and Aβ 5–16 . Using CD and UV–vis spectroscopies and potentiometry, we found that all peptides coordinated the Cu(II) ion with substantial affinities higher than 3 × 10 12 M –1 at pH 7.4 for Aβ 5–9 and Aβ 5–12 . This affinity was elevated 3-fold in Aβ 5–16 by the formation of the internal macrochelate with the fourth coordination site occupied by the imidazole nitrogen of the His13 or His14 residue. A much higher boost of affinity could be achieved in Aβ 5–9 and Aβ 5–12 by adding appropriate amounts of the external imidazole ligand. The 3N Cu-Aβ 5– x complexes could be irreversibly reduced to Cu(I) at about −0.6 V vs Ag/AgCl and oxidized to Cu(III) at about 1.2 V vs Ag/AgCl. The internal or external imidazole coordination to the 3N core resulted in a slight destabilization of the Cu(I) state and stabilization of the Cu(III) state. Taken together these results indicate that Aβ 5– x peptides, which bind Cu(II) ions much more strongly than Aβ 1– x peptides and only slightly weaker than Aβ 4– x peptides could interfere with Cu(II) handling by these peptides, adding to copper dyshomeostasis in Alzheimer brains.

Intermediate Cu(II)-Thiolate Species in the Reduction of Cu(II)GHK by Glutathione: A Handy Chelate for Biological Cu(II) Reduction

“…Large blue shifts (typically 40–60 nm) were observed in 3 + 1N ternary Cu(II) complexes formed by GHK and other XH-type peptides with imidazole rings, with much smaller shifts observed for 3N + 1O complexes. 1 , 49 − 51 An intermediate shift detected here (10–12 nm) could be due to a partial formation of a 3 + 1N ternary species with another GHK molecule, GHK-Cu(II)GHK, 1 as a consequence of an increased excess of GHK over Cu(II) ions, depleted by partial reduction to Cu(I).…”

Impact of N‐Truncated Aβ Peptides on Cu‐ and Cu(Aβ)‐Generated ROS: CuI Matters!

“…As for the Cu II (Aβ 4–16 ), the Cu II (Aβ 11–16 ) can be oxidized to Cu III (Aβ 11–16 ) at E pa =0.78 V vs. SCE (1.02 V vs. NHE) but this time the Cu III species can be reduced at E pa =0.67 V vs. SCE (0.91 V vs. NHE) leading to a quasi‐reversible process. The reversibility of the Cu(III/II) process in the ATCUN motif is dependent on the nature of the Xxx and Zzz amino acid residues, which can explain the difference with Cu II (Aβ 4–16 ) in addition to the absence of the concomitant oxidation of Tyr10 [7b, 29] . Cu II (Aβ 11–16 ) shows an irreversible cathodic peak at E pc =−1.26 V vs. SCE (−1.50 V vs. NHE) attributed to its reduction followed by a structural rearrangement leading to a re‐oxidation peak at E pa =0.27 V vs. SCE (0.51 V vs. NHE), as observed for Cu II (Aβ 4–16 ).…”

Tuning Receptor Properties of Metal–Amyloid Beta Complexes. Studies on the Interaction between Ni(II)–Aβ5–9 and Phosphates/Nucleotides

“…These values are in agreement with a previous determination. 12 As described in Table 1 in a descending order, they are associated with the protonation/deprotonation of the N-terminal amine, the imidazole ring of His2, and the carboxyl group of Asp3.…”

“…Assignments are based on literature values. 12 , 18 , 24 c Calculated based on the distribution diagram presented in Figure 1 . …”