The interactome of the copper transporter ATP7A belongs to a netowrk of neurodevelopmental and neurodegeneration factors
The interactome of the copper transporter ATP7A belongs to a netowrk of neurodevelopmental and neurodegeneration factors
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DOI：
10.7554/elife.24722
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发表时间：
2017-03-29
期刊：
影响因子：
7.7
通讯作者：
Faundez, Victor
中科院分区：
文献类型：
--
作者：
Comstra, Heather S.;McArthy, Jacob;Faundez, Victor
遗传和环境因素，如金属，相互作用，以确定神经特征。我们推断，神经元中处理金属的分子的相互作用组应该包括新的金属稳态途径。我们专注于铜及其转运蛋白ATP7A，因为ATP7A无效突变会导致神经退行性变。我们进行了ATP7A免疫亲和层析，并确定了541蛋白与ATP7A共分离。ATP7A相互作用组集中的基因产物涉及神经变性和神经发育障碍，包括高尔基体定位的保守寡聚体高尔基体（COG）复合物的亚基。COG空细胞具有改变的ATP 7A和CTR 1（SLC31A1）的含量和亚细胞定位，铜摄取所需的转运蛋白，以及减少的总细胞铜，和受损的铜依赖性代谢反应。果蝇神经元中ATP 7A和COG亚基表达的变化改变了幼虫的突触发育和铜诱导的成年果蝇死亡率。我们的结论是，ATP7A相互作用组包括一个新的COG依赖性机制，以指定神经元的发育和生存。
Genetic and environmental factors, such as metals, interact to determine neurological traits. We reasoned that interactomes of molecules handling metals in neurons should include novel metal homeostasis pathways. We focused on copper and its transporter ATP7A because ATP7A null mutations cause neurodegeneration. We performed ATP7A immunoaffinity chromatography and identified 541 proteins co-isolating with ATP7A. The ATP7A interactome concentrated gene products implicated in neurodegeneration and neurodevelopmental disorders, including subunits of the Golgi-localized conserved oligomeric Golgi (COG) complex. COG null cells possess altered content and subcellular localization of ATP7A and CTR1 (SLC31A1), the transporter required for copper uptake, as well as decreased total cellular copper, and impaired copper-dependent metabolic responses. Changes in the expression of ATP7A and COG subunits in Drosophila neurons altered synapse development in larvae and copper-induced mortality of adult flies. We conclude that the ATP7A interactome encompasses a novel COG-dependent mechanism to specify neuronal development and survival.