| Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes. | |
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MedLine Citation:
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PMID: 18650808 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Copper is a cofactor for many cellular enzymes and transporters. 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, respectively. Endomembrane cuproproteins are thought to incorporate copper stably on transit through the trans-Golgi network, in which ATP7A accumulates by dynamic cycling through early endocytic compartments. 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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Authors:
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Subba Rao Gangi Setty; Danièle Tenza; Elena V Sviderskaya; Dorothy C Bennett; Graça Raposo; Michael S Marks |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-07-23 |
Journal Detail:
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Title: Nature Volume: 454 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-29 Completed Date: 2008-09-23 Revised Date: 2011-01-24 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 1142-6 Citation Subset: IM |
Affiliation:
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Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphatases
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metabolism* Animals Carrier Proteins / genetics, metabolism Cation Transport Proteins / metabolism* Cell Line Copper / metabolism*, pharmacology Endosomes / metabolism Humans Melanocytes / cytology, drug effects, enzymology, metabolism Melanosomes / drug effects, enzymology*, metabolism Mice Monophenol Monooxygenase / metabolism* Organ Specificity Qa-SNARE Proteins / metabolism Tyrosine / metabolism* trans-Golgi Network / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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064583//Wellcome Trust; R01 EY015625/EY/NEI NIH HHS; R01 EY015625-05/EY/NEI NIH HHS; R21 GM078474/GM/NIGMS NIH HHS; R21 GM078474-02/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Cation Transport Proteins; 0/Qa-SNARE Proteins; 55520-40-6/Tyrosine; 7440-50-8/Copper; EC 1.14.18.1/Monophenol Monooxygenase; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.3.4/Atp7a protein, mouse |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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