Kinetics of Cu(ii) complexation by ATCUN/NTS and related peptides: a gold mine of novel ideas for copper biology

Abstract

The aim of this perspective is to help revive studies of the kinetics of formation and exchange in Cu(ii)–peptide complexes. Such studies have the power to reveal novel reactive intermediates and set timeframes for actual physiological processes.

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer’s-Related Aβ Peptide

“…The formation of Cu(AAH) is at least 20 times slower than that of Cu(AH). To account for this difference, we have to take into consideration very recent reports on the kinetics of formation of ATCUN Cu II complexes [ 81 , 82 , 83 , 84 , 85 , 86 ]. It proceeds via several successive steps: anchoring of the Cu II by the imidazole ring of His, then formation of a metallacycle with the anchoring of the N-terminal amine, leading to the 2N intermediate ( Scheme S2 for a drawing of the various intermediates described in this work) and rearrangement of the 4N ATCUN motif [ 81 ].…”

The rates of Cu(ii)–ATCUN complex formation. Why so slow?

“…This finding is consistent with our previous proposal that the IC to 4N transition rate in GGH, and presumably other ATCUN peptides, is controlled by conformational equilibria in the IC. 1,10 To conclude, in this study we systematically analysed the effect of the 1 st and 2 nd sphere on the rate of formation of cupric 4N ATCUN complexes, first reported for the GGH tripeptide. 10 Data for GGH analogues with respective nitrogen atoms excluded from Cu(II) binding revealed that despite the absence of a chelate effect, the formation of a metastable IC complex with {NH 2 + N Im } coordination is more than a hundred-fold faster than the {NH 2 + N − } or {N − + N Im } alternatives.…”

“…A knowledge of reaction rates can help clarify such issues in copper physiology, as its cellular uptake or contribution to Alzheimer's disease pathology. 1 In biological processes the Cu( ii ) ions ought to be exchanged between different protein partners within strict timeframes. For instance, the hCTR1 cellular transporter apparently requires just 100 ms to deliver a copper ion to a cell, 2 while Cu( ii ) release and reuptake in the synaptic cleft occur within a few milliseconds.…”

“…albumin (N-terminal sequence DAH), 7 copper importer hCtr-1 (MDH) 8 or Aβ 4− x peptides (FRH), 9 exhibit pico- to femtomolar Cu 2+ affinities at pH 7.4. 1,5 However, despite the vast knowledge about Cu( ii ) complexes with these and other ATCUN sequences, obtained from potentiometric, spectroscopic (UV-Vis, CD), structural (X-ray, NMR, EXAFS) or electrochemical studies, little is known about the mechanisms and rates of their formation.…”

“…This finding is consistent with our previous proposal that the IC to 4N transition rate in GGH, and presumably other ATCUN peptides, is controlled by conformational equilibria in the IC. 1,10…”