Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes

Copper is an important cofactor for several enzymes. In order to be loaded onto endomembrane proteins, it is translocated from the cytosol by the copper transporters ATP7A or ATP7B. It is thought that proteins acquire copper upon transit through the trans Golgi network. Setty et al. study copper transport in pigment forming cells, mouse melanocytes. The enzyme tyrosinase catalyses melanin synthesis in melanosomes and requires copper for its activity. They find that while tyrosinase acquires copper within the trans Golgi network, it is inefficient and is lost within intermediate trafficking vesicles. Tyrosinase is subsequently reloaded with copper only when it reaches melanocytes by the copper transporter ATP7A. This provides a system for cell type specific spatial control of metalloenzyme activity and prevents aberrant activation of tyrosinase during transport. Copper is a cofactor for many cellular enzymes and transporters1. It can be loaded onto secreted and endomembrane cuproproteins by translocation from the cytosol into membrane-bound organelles by ATP7A or ATP7B transporters, the genes for which are mutated in the copper imbalance syndromes Menkes disease and Wilson disease, respectively2. Endomembrane cuproproteins are thought to incorporate copper stably on transit through the trans-Golgi network, in which ATP7A accumulates3 by dynamic cycling through early endocytic compartments4. Here we show that the pigment-cell-specific cuproenzyme tyrosinase acquires copper only transiently and inefficiently within the trans-Golgi network of mouse melanocytes. To catalyse melanin synthesis, tyrosinase is subsequently reloaded with copper within specialized organelles called melanosomes. Copper is supplied to melanosomes by ATP7A, a cohort of which localizes to melanosomes in a biogenesis of lysosome-related organelles complex-1 (BLOC-1)-dependent manner. These results indicate that cell-type-specific localization of a metal transporter is required to sustain metallation of an endomembrane cuproenzyme, providing a mechanism for exquisite spatial control of metalloenzyme activity. Moreover, because BLOC-1 subunits are mutated in subtypes of the genetic disease Hermansky–Pudlak syndrome, these results also show that defects in copper transporter localization contribute to hypopigmentation, and hence perhaps other systemic defects, in Hermansky–Pudlak syndrome.