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

Copper is a cofactor for many cellular enzymes and transporters. To be loaded onto secreted and endomembrane cuproproteins, copper is translocated from the cytosol into membrane‐bound organelles by one of two transporters, ATP7A or ATP7B, the genes for which are mutated in the copper imbalance syndromes, Menkes and Wilson disease, respectively. Endomembrane cuproproteins are thought to stably incorporate copper upon transit through the trans Golgi network (TGN), within which ATP7A and ATP7B accumulate in most cells by dynamic cycling through early endocytic compartments. Here we show that the pigment cell‐specific cuproenzyme tyrosinase acquires copper only transiently within the TGN of melanocytes. To catalyze melanin synthesis, tyrosinase must be subsequently reloaded with copper within specialized pigment 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 cell type‐specific spatial control of metalloenzyme activity. Moreover, as BLOC‐1 subunits are mutated in subtypes of the genetic disease, Hermansky‐Pudlak syndrome (HPS), these results also show that defects in copper transporter localization contribute to hypopigmentation, and hence perhaps other systemic defects, in HPS.