Structure and mechanism of the human copper transporting ATPases: Fitting the pieces into a moving puzzle

Human copper transporters ATP7B and ATP7A deliver copper to biosynthetic pathways and maintain copper homeostasis in the cell. These enzymes combine several challenges for structural biology because they are large low abundance membrane proteins with many highly mobile domains and long disordered loops. No method has yet succeeded in solving the structure of the complete fully functional protein. Still, X-ray crystallography, Cryo-EM and NMR helped to piece together a structure based model of the enzyme activity and regulation by copper. We review the structures of ATP7B and ATP7A with an emphasis on the mechanistic insights into the unique aspects of the transport function and regulation of the human copper ATPases that have emerged from more than twenty years of research.