Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes.
Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes.
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DOI：
10.1038/nature07163
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发表时间：
2008-08-28
期刊：
影响因子：
64.8
通讯作者：
Marks, Michael S.
中科院分区：
文献类型：
--
作者：
Setty, Subba Rao Gangi;Tenza, Daniele;Sviderskaya, Elena V.;Bennett, Dorothy C.;Raposo, Graca;Marks, Michael S.
铜是许多细胞酶和转运蛋白的辅因子。为了加载到分泌和内膜铜蛋白上，铜通过ATP 7A或ATP 7 B转运蛋白从细胞质转运到膜结合的细胞器中，所述转运蛋白的基因分别在铜失衡综合征、门克斯病和威尔逊病中突变。内膜铜蛋白被认为是稳定地纳入铜转运后，通过transGolgi网络（TGN），其中ATP 7A积累的动态循环通过早期内吞隔室。在这里，我们表明，色素细胞特异性铜酶酪氨酸酶获得铜只有短暂的和低效的黑素细胞的TGN内。为了催化黑色素合成，酪氨酸酶随后在称为黑素体的专门细胞器中重新装载铜。铜通过ATP 7A提供给黑素体，ATP 7A的一个群组以溶酶体相关细胞器复合物-1（BLOC-1）依赖性方式生物发生定位于黑素体。这些结果表明，细胞类型特异性定位的金属转运蛋白是必需的，以维持代谢的内膜铜酶，提供了一种机制，精致的空间控制金属酶的活性。此外，由于BLOC-1亚基在遗传性疾病Hermansky-Pudlak综合征（HPS）的亚型中发生突变，这些结果也表明铜转运蛋白定位缺陷导致HPS中色素减退，因此可能导致其他全身性缺陷。
Copper is a cofactor for many cellular enzymes and transporters. To load onto secreted and endomembrane cuproproteins, copper is translocated from the cytosol into membrane-bound organelles by ATP7A or ATP7B transporters, 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 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 TGN of melanocytes. To catalyze 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, 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.
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