Publication Date:
2008-07-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812007/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812007/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Setty, Subba Rao Gangi -- Tenza, Daniele -- Sviderskaya, Elena V -- Bennett, Dorothy C -- Raposo, Graca -- Marks, Michael S -- 064583/Wellcome Trust/United Kingdom -- 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/ -- England -- Nature. 2008 Aug 28;454(7208):1142-6. doi: 10.1038/nature07163. Epub 2008 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18650808" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Triphosphatases/*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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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