A Copper Story: From Protein Folding and Metal Transport to Cancer

Abstract

Enzymes need to fold into unique three‐dimensional structures in order to function. Copper ions are cofactors in many essential enzymes. Such enzymes need to couple polypeptide folding with metal incorporation, as the metal sites are often integrated within the folded structure. Since free copper ions are toxic, most organisms have highly specialized copper transport systems. The human cytoplasmic copper chaperone Atox1 delivers copper to P1B‐type ATPases in the Golgi, for incorporation into copper‐dependent enzymes following the secretory path. Copper plays key roles in cancer development, as copper‐dependent enzymes are needed for tumor growth and metastasis. In addition, platinum‐based drugs are exported out of cells by the copper transport machinery. Recent findings also imply that some copper transport proteins regulate cell growth and development. In this brief journey of my later career, I will discuss the roles of copper in protein folding, mechanisms of copper ion transport, and cisplatin hitchhiking. The identification of new partners for Atox1 underscore the importance of further research in this area for combating cancer.

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

“…ATP7B is also responsible for excretion of Cu through the bile duct. For more detailed information please refer to the following reviews [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

Differences in the mechanical unfolding pathways of apo- and copper-bound azurins

“…Azurin, in particular, shows a strong absorption band with maximum around 625 nm due to S(cys)→Cu 2+ ligand-to-metal charge transfer transition 24 . The exact function of azurin and the role of copper are not known, although in vitro studies suggest that azurin may function as a redox shuttle, facilitating electron transfer in denitrification and/or respiration chains 25 , 26 . Azurin is an interesting metalloprotein system, where copper-binding does not change the protein structure 22 , 23 .…”

“…It appears that the polypeptide fold of apo-azurin has a preformed copper binding site and the binding of copper induces very little change in both, the positions of residues at the metal binding site, and the overall structure of protein (see Fig. S1 ) 26 . Despite the negligible perturbation in protein structure, we demonstrate using SMFS and SMD that the copper ion (Cu 2+ ) alters the unfolding energy landscape of azurin.…”