A Functional Role for Aβ in Metal Homeostasis? N‐Truncation and High‐Affinity Copper Binding

Abstract

Accumulation of the β-amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimer's disease (AD). The Aβ1-x (x=16/28/40/42) peptides have been the primary focus of Cu(II) binding studies for more than 15 years; however, the N-truncated Aβ4-42 peptide is a major Aβ isoform detected in both healthy and diseased brains, and it contains a novel N-terminal FRH sequence. Proteins with His at the third position are known to bind Cu(II) avidly, with conditional log K values at pH 7.4 in the range of 11.0-14.6, which is much higher than that determined for Aβ1-x peptides. By using Aβ4-16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds Cu(II) with a conditional Kd value of 3×10(-14) M at pH 7.4, and that both Aβ4-16 and Aβ4-42 possess negligible redox activity. Combined with the predominance of Aβ4-42 in the brain, our results suggest a physiological role for this isoform in metal homeostasis within the central nervous system.

Tuning the Redox Properties of Copper(II) Complexes with Amyloid-β Peptides

“…1A). As expected, 21 there were no peaks in the range of positive potentials characteristic of a Cu(II)/Cu(III) process for Cu(II)-Aβ(1-16), while CV recorded at lower potentials (Fig. 1B) revealed a completely irreversible Cu(II)/(I) redox process with a very slow electron transfer (separation between cathodic and anodic peaks was ca.…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[103,104] Such affinity is perfectly in line with those of other ATCUN peptides. [109,110] Note that a secondary Cu II site is present in A [4][5][6][7][8][9][10][11][12][13][14][15][16] and is relatively weak (K a = 10 6.7 M -1 at pH = 7.4) and separated from the N-terminal site.…”

“…More generally, N-terminally truncated peptides might also be considered for new therapeutic targets. [9] To conclude, and as previously pointed out in seminal works, [103,104,111,134,136] the interaction of Cu II with N-terminally truncated peptides might reshape our current view of the deleterious impact of Cu II binding to amyloid-peptides.…”

“…[77,97,98] The ATCUN coordination mode of Cu II to A 4-n and to A 11-n is predominant from pH 5, whereas deprotonation of outer-sphere and non-binding side chains occurs when the pH is increased. [103][104][105] A weak fifth ligand, a water molecule, can be present as an apical ligand. This coordination is analogous to the one proposed for the DAHK tetrapeptide, the N-terminal sequence of human serum albumin, the structure of which was resolved by means of X-ray diffraction.…”

“…[109,110] Note that a secondary Cu II site is present in A [4][5][6][7][8][9][10][11][12][13][14][15][16] and is relatively weak (K a = 10 6.7 M -1 at pH = 7.4) and separated from the N-terminal site. [103] The affinity for Cu II -more than three orders of magnitude higher than the full-length peptides -make these peptides key biological partners in the trafficking of Cu II within the synaptic cleft.…”