1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
2. Institut Curie, Centre de Recherche, Paris F-75248, France
3. Centre National de la Recherche Scientifique, UMR 144, Paris F-75248, France
4. Centre for Molecular and Metabolic Signalling, Division of Basic Medical Sciences, St George's, University of London, London SW17 0RE, UK

Correspondence to: Michael S. Marks¹ Correspondence and requests for materials should be addressed to M.S.M. (Email: marksm@mail.med.upenn.edu).

Abstract

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.

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