Document Detail

Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes.
MedLine Citation:
PMID:  18650808     Owner:  NLM     Status:  MEDLINE    
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.
Subba Rao Gangi Setty; Danièle Tenza; Elena V Sviderskaya; Dorothy C Bennett; Graça Raposo; Michael S Marks
Related Documents :
23119928 - Rhinitis caseosa, nasal cholesteatoma and allergic fungal sinusitis.
19912978 - From autoimmune enteropathy to the ipex (immune dysfunction, polyendocrinopathy, entero...
11407658 - Clinical genetics of multiple endocrine neoplasias, carney complex and related syndromes.
15367858 - Congenital myasthenic syndromes.
17446798 - Relationship between phytosterol levels and components of the metabolic syndrome in the...
8042668 - Scalp-ear-nipple syndrome: additional manifestations.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-07-23
Journal Detail:
Title:  Nature     Volume:  454     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-29     Completed Date:  2008-09-23     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  1142-6     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adenosine Triphosphatases / metabolism*
Carrier Proteins / genetics,  metabolism
Cation Transport Proteins / metabolism*
Cell Line
Copper / metabolism*,  pharmacology
Endosomes / metabolism
Melanocytes / cytology,  drug effects,  enzymology,  metabolism
Melanosomes / drug effects,  enzymology*,  metabolism
Monophenol Monooxygenase / metabolism*
Organ Specificity
Qa-SNARE Proteins / metabolism
Tyrosine / metabolism*
trans-Golgi Network / metabolism
Grant Support
064583//Wellcome Trust; R01 EY015625/EY/NEI NIH HHS; R01 EY015625/EY/NEI NIH HHS; R01 EY015625-05/EY/NEI NIH HHS; R21 GM078474/GM/NIGMS NIH HHS; R21 GM078474/GM/NIGMS NIH HHS; R21 GM078474-02/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Carrier Proteins; 0/Cation Transport Proteins; 0/Qa-SNARE Proteins; 42HK56048U/Tyrosine; 789U1901C5/Copper; EC Monooxygenase; EC 3.6.1.-/Adenosine Triphosphatases; EC protein, mouse

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  A blend of small molecules regulates both mating and development in Caenorhabditis elegans.
Next Document:  Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U).