Why a copper-transporting protein is needed for healthy nerves
A copper transporter interacts with hundreds of proteins, including many known to support nerves and brain activity.
People need a source of copper in their diet because this nutrient is used to produce the pigment in hair and skin, the connective tissue in tendons and ligaments, and some of the small molecules that allow brain cells to communicate. There is an ideal range of copper that allows cells to carry out these processes. Both too much and too little copper can have negative effects on health, particularly related to how the brain works.
Cells contain multiple proteins that bind to copper and transport it wherever it is needed. People with mutations that mean they lack one of these copper transporters, ATP7A, often have serious damage to their nervous system that cannot be explained by the current understanding of how this protein works.
Heather Comstra and co-workers set out to establish a comprehensive list of proteins that interact with ATP7A to better understand how this transporter works and how it is regulated. The search revealed that ATP7A interacts with hundreds of proteins present in different compartments within cells, many of which had not previously been associated with balancing copper levels in cells and the body. Like ATP7A, many of these proteins (or the protein complexes that contain them) are known to affect nerves and brain activity when they are mutated.
Next, Comstra and co-workers engineered human cells grown in the laboratory to lack one of the protein complexes that interacts with ATP7A, the COG complex. Cells without this protein complex had 50% less ATP7A than normal human cells and very low levels of copper too. These mutant cells also had problems generating the energy that they need, because the structures in cells that provide them with energy — the mitochondria — were impaired; adding copper to the cells improved the activity of their mitochondria.
Mutations in the COG complex cause the brain to develop abnormally, and the finding that deleting the COG complex from cells causes copper deficiency now helps to explain why. Further characterization of the proteins that interact with ATP7A and the COG complex will contribute to our understanding of how cells regulate copper and how copper levels affect the brain.
To find out more
Read the eLife research paper on which this eLife digest is based: “The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors” (March 29, 2017).
