Chem. Commun. [BCB]

Summary :

Copper and zinc trafficking in and around cells, mainly between proteins, is a very fundamental and essential process in most living organisms and impairment of such trafficking can be lethal, like well documented in the genetic Cu-overload Wilson  diseases. Moreover, the metabolism of these essential metal ions Cu and Zn are connected (e.g. Wilsons disease can be treated by Zn supplementation), although the molecular mechanisms are little described.

Another disease in which Cu and Zn seems to play a role is Alzheimer’s disease. A key peptide of Alzheimer’s disease (AD) is called amyloid-beta (Abeta). This peptides accumulate in AD in form of plaques, consisting mainly of aggregated Abeta and contain also high amount of Cu and Zn. Abeta occurs under different peptide-length. Recently, the highly abundant truncated form Abeta4-40/42 came into focus, because its affinity to Cu is more than 3 order of magnitudes higher than the classical Abeta1-40/2.

It has been suggested that Cu and Zn-binding to Abeta can contribute to AD, via Zn or Cu induced structural changes and formation of more toxic aggregates and for Cu via catalyzing the production of reactive oxygen species.

Thus the metal-transfer reaction of Cu and Zn, from and to Abeta, seems to be pivotal. In this respect, a main and highly abundant protein is from the family of Metallothioneins, in particular the most brain-specific form, Metallothionein-3 (MT-3). MT-3 binds classically 7 Zn(II)-ions, but recently the importance of partially loaded MTs became evident, as they are able to buffer the Zn-concentration.

In the present communication we report that the physiological relevant amino acid glutamate (a neurotransmitter) is able to accelerate the Cu-transfer from Abeta4-16 (model for Abeta4-40/42) to Zn₇-MT-3. Moreover, we show that this Cu-transfer is also accelerated by the chelator EDTA. EDTA withdraws Zn from MT-3, leading to partially Zn-loaded MT species, which undergo a faster Cu-transfer. This mechanism is different from the one exerted by glutamate, which interacts with Cu bound to Abeta. Adding glutamate and EDTA further accelerates the Cu-transfer, in line with an additive effect of two different mechanisms.

Partially Zn(II)-loaded MT-3 species are physiological relevant and can be formed by Zn-binding proteins with an affinity similar or higher than MT-3. Thus Zn-load of MT-3 depends on the Zn-status of a given compartment, which might then be able to influence the Cu trafficking. This is an interesting mechanism that couples copper and zinc metabolism.

Graphical Abstract:

Reference:

Alice Santoro, Nina Ewa Wezynfeld, Ewelina Stefaniak, Adam Pomorski, Dawid Płonka, Artur Krezel, Wojciech Bal and Peter Faller

Cu transfer from amyloid-β_4–16 to metallothionein-3: the role of the neurotransmitter glutamate and metallothionein-3 Zn(II)-load states

Chem. Commun., Accepted 15th October 2018 - DOI : 10.1039/c8cc06221h

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