Hierarchical binding of copperII to N-truncated Aβ4–16 peptide

Abstract

Multiple intermediates were found in Cu(ii) binding to Aβ4–16 before the formation of a tight complex.

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

“…In a quasi‐stoichiometric amount of Cu II (0.9 equiv per peptide) and at about 0.5 m m , Aβ 11–16 is faster in coordinating Cu II than Aβ 4–16 , with t 1/2 =0.13±0.02 s vs. t 1/2 =0.45±0.1 s for Aβ 11–16 and Aβ 4–16 , respectively. The value found for Aβ 4–16 agrees fairly well with that recently determined by competition and double mixing stopped‐flow experiments and attributed to the formation of the Cu II (Aβ 4–16 ) ATCUN motif once the Cu II is anchored to the peptide [21] . Additionally, the value found for Cu II (Aβ 11–16 ) is consistent with the value very recently determined [22] for the short GGH peptide by classical stopped‐flow experiments and attributed to the reshuffling of the Cu II site forming the ATCUN motif after initial anchoring to the N‐terminal and side‐chain of His groups.…”

“…). However we can propose a linearly bound Cu II species in which the Cu II might be linked by two His (reminiscent from Cu I site) or by one His and the N‐terminal amine, based on recent articles aimed at deciphering the first species appearing during the formation of Cu II (Aβ 4–16 ) ATCUN [21] and Cu II (GGH) ATCUN [22] In the presence of Cu II (Aβ 1–16 ), the time required for Cu II to become bound inside the N ‐truncated peptides is at least one order of magnitude longer than for Cu II (compare Figures S1 and S8) and there is no ROS produced provided that the mixture time between Cu II (Aβ 1–16 ) and the Aβ 4/11–16 is long enough.…”

“…). However we can propose a linearly bound Cu II species in which the Cu II might be linked by two His (reminiscent from Cu I site) or by one His and the N‐terminal amine, based on recent articles aimed at deciphering the first species appearing during the formation of Cu II (Aβ 4–16 ) ATCUN [21] and Cu II (GGH) ATCUN [22] …”

The Aggregation Pattern of Aβ1–40 is Altered by the Presence of N‐Truncated Aβ4–40 and/or CuII in a Similar Way through Ionic Interactions

“…In line with these observations, a very strong resistance of Cu II –Aβ 4–16 to reductively release copper to metallothionein has also been reported [54, 55] . Cu II –Aβ 4–16 is also kinetically inert in non‐redox exchange reactions [56, 57] . These findings prompted the concept that, in the brain, Aβ 4–42 may participate in a separate pathway involving divalent copper trafficking, possibly clearing the synaptic cleft from Cu II leftovers during neurotransmission [42, 58] .…”

“…[54,55] Cu II -Ab 4-16 is also kinetically inert in non-redoxe xchange reactions. [56,57] These findings prompted the concept that, in the brain, Ab 4-42 may participate in as eparate pathway involving divalent copper trafficking, possibly clearing the synaptic cleft from Cu II leftoversd uring neurotransmission. [42,58] This concept is further supported by the finding that the short Ab 4-9 peptide, the prominent product of the neprilysin cleavage of Ab 1-40 ,f ormed aC u II complex with an inertness and affinity even higherthan that of Ab 4-16 (log K = 14.2 at pH 7.4).…”