Université de Strasbourg

26th USIAS Fellows seminar - Towards a membrane penetrating copper shuttle

October 18, 2016
From 12:30 until 14:00

By Peter Faller, USIAS Fellow 2015

The metal content of living organisms is normally lower than the most abundant elements oxygen (O), hydrogen (H), carbon (C) and nitrogen (N). The most abundant metals are sodium, potassium, magnesium and calcium, which contribute to 0.05 to 1.5% of the body-weight in humans. Other metals are even less abundant. Copper (Cu) and iron (Fe) content is only about 0.07 and 4 g per 70 kg human body.

Despite this low content, several metal ions including Fe and Cu, are essential; this means their absence is lethal. So one can ask the question why we do need this low amount of metals at all? The answer is that they can do chemistry that the more abundant compounds mainly made of O, C, N etc. cannot due. By doing this chemistry, they perform essential biological functions.

An example is the conversion of energy in the respiratory chain or the transport of dioxygen. To do that, the metals like Cu and Fe are embedded in proteins and enzymes to exert this function. This is very important as the protein scaffold controls the type of reaction the metal does. Indeed Cu and Fe are very powerful catalyst and can also catalyze unwanted or dangerous reactions.

Thus the metabolism of Cu and Fe is very is tightly controlled, in order to assure that Cu is at the right place, at the right time and in the right concentration. Copper mismetabolism can be lethal, as witnessed by the two genetic disorders relating to copper transporters, leading either to copper overload (Wilson’s disease) or to copper deficiency (Menkes disease). An important mechanism for toxicity in the copper overload is the capability of “wrongly” or loosely bound copper to catalyze the production of reactive oxygen species, which can destroy biomolecules.

Mismetabolism of copper has been reported in several neurodegenerative diseases, such as Alzheimer’s disease. Cu was found to be bound to the Alzheimer specific amyloid plaques, where Cu is bound to the peptide amyloid-β (Aβ). Complexes of Cu-Aβ are able to catalyze the production of reactive oxygen species and are hence potential dangerous. From this observation it was proposed that this Cu is misplaced and should be removed from extracellular Aβ and transported back into the cell. In this context our project aims to elaborate peptide based molecules able to transport Cu from Aβ back into the cell. To do this the Cu has to cross the cell membrane and Cu has to be released once the transporter peptide arrived in the cell. At the moment we work on the second aspect, the first one is scheduled soon.

Figure: image amyloid-β fibrils obtained by atomic force microscopy. Such type of fibers are found in the amyloid plaques of Alzheimer’s disease patients where they contain copper ions.

This seminar will present the ongoing research in the joint project Peptides as biological shuttles for copper ions by Peter Faller and Christelle Hureau, USIAS Fellows 2015.

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