Resistance of Cu(Aβ4–16) to Copper Capture by Metallothionein‐3 Supports a Function for the Aβ4–42 Peptide as a Synaptic Cu^II Scavenger

Abstract

Aβ4-42 is a major species of Aβ peptide in the brains of both healthy individuals and those affected by Alzheimer's disease. It has recently been demonstrated to bind Cu(II) with an affinity approximately 3000 times higher than the commonly studied Aβ1-42 and Aβ1-40 peptides, which are implicated in the pathogenesis of Alzheimer's disease. Metallothionein-3, a protein considered to orchestrate copper and zinc metabolism in the brain and provide antioxidant protection, was shown to extract Cu(II) from Aβ1-40 when acting in its native Zn7 MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7 MT-3 against Aβ toxicity. In this work, we used the truncated model peptides Aβ1-16 and Aβ4-16 to demonstrate that the high-affinity Cu(II) complex of Aβ4-16 is resistant to Zn7 MT-3 reactivity. This indicates that the analogous complex of the full-length peptide Cu(Aβ4-42) will not yield copper to MT-3 in the brain, thus supporting the concept of a physiological role for Aβ4-42 as a Cu(II) scavenger in the synaptic cleft.

Crosstalk of the structural and zinc buffering properties of mammalian metallothionein-2

“…The culture medium (1.1% tryptone, 2.2% yeast extract, 0.45% glycerol, 1.3% K 2 HPO 4 , 0.38% KH 2 PO 4 ) was prepared as described previously. 30,31 Transformed bacteria (4 l) were cultured at 37 1C until OD 600 reached 0.5, then induced with 0.1 mM IPTG and incubated overnight at 20 1C with vigorous shaking. All subsequent steps of purification were conducted at 4 1C.…”

“…So, a minimum of 3 and a maximum of 5 cysteine residues would be involved in Zn(II) coordination. Tryptic fragment [26][27][28][29][30][31] with two cysteines is observed as singly modified, so the other cysteine might be involved in metal binding to fill up Zn(II) coordination in the b-domain. MD simulations present a structure with Zn 4 S 11 and ZnS 4 clusters in a-and b-domains, respectively ( Fig.…”

“…1b, b-cluster). The most abundant fourfold modified tryptic fragment [21][22][23][24][25][26][27][28][29][30][31] of bMT2 from a 1 eq. Zn(II) sample indicates modified Cys21, 24, 26 and 29 residues, and the triply modified tryptic fragment [23][24][25][26][27][28][29][30][31] from the same sample confirms Cys24, 26 and 29 modifications (Fig.…”

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

“…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.…”

“…It has been shown that Cu(A 4-x ) can only be oxidized and at relatively high cathodic potential (0.8 V versus a saturated calomel electrode, SCE) and that, in line with these redox properties, it does not yield ROS under biologically relevant conditions. [111] The other truncated ATCUN-type A peptides, A 11-x , might have properties similar to those of A . However, it remains to be determined if the ATCUN site of A 11-x peptides can undergo redox cycling and generate ROS.…”