The strict regulation of copper metabolism ensures that there is an adequate amount of copper available for uptake, while at the same time the toxic properties of copper have to be restricted.
Peter van den Berghe has developed a new copper sensor in order to measure changes in copper metabolism. With the help of this copper sensor, he was first able to determine how copper is transported into cells. To this end, he studied the function of two homologous proteins: hCTR1 and hCTR2 that are used in copper import. These two copper transporters vary in their affinity for copper and are situated in various cell organelles. This suggests that cells can recruit copper from different pools. Both copper transporters form trimers and are dependent on this process for their copper transport function.
Wilson’s disease is caused by mutations in the gene that codes for ATP7B, a copper export pump. A surprisingly large number of ATP7B mutants were misfolded, as was apparent from the fact that they were poorly expressed and trapped by the endoplasmic reticulum. Four different ATP7B-mutants showed residual copper export capacity. Treatment with the pharmacological chaperones of curcumin, and 4-phenylbutyrate used in clinical practice, was able to normalize the protein expression and the locations of these ATP7B-mutants. Therefore, the use of these chaperones may be promising in the future for improving the folding, positioning and function of ATP7B in these patients.
Peter van den Berghe will receive his PhD from Utrecht University on April 29.