Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation
Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation
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DOI：
10.1038/sj.emboj.7600566
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发表时间：
2005-02-23
期刊：
影响因子：
11.4
通讯作者：
Walz, G
中科院分区：
文献类型：
--
作者：
Köttgen, M;Benzing, T;Walz, G
离子通道向质膜的运输受到严格控制，以确保细胞内离子稳态和信号转导的适当调节。多囊蛋白- 2是阳离子通道TRP家族的一员，其突变可导致常染色体显性多囊肾病，多囊肾病是一种以肾囊肿和进行性肾功能衰竭为特征的疾病。多囊蛋白- 2作为钙渗透性非选择性阳离子通道；然而，关于多囊蛋白- 2是存在于质膜还是内质网，存在争议。我们发现，多囊蛋白- 2的亚细胞定位和功能是由磷酸丝氨酸酸性簇分选蛋白(PACS)- 1和PACS- 2指导的，这两个接头蛋白识别多囊蛋白- 2羧基末端的酸性簇。与这些接头蛋白的结合是由蛋白激酶酪蛋白激酶2对多囊蛋白- 2的磷酸化调节的，这是多囊蛋白- 2在内质网、高尔基体和质膜间室之间传递所必需的。我们认为多囊蛋白- 2在内质膜和质膜上都有活性，这与之前关于其定位和功能的不一致观点相一致。此外，PACS蛋白可能代表了离子通道运输的一种新的分子机制，将酸性含簇离子通道导向不同的亚细胞区室。
The trafficking of ion channels to the plasma membrane is tightly controlled to ensure the proper regulation of intracellular ion homeostasis and signal transduction. Mutations of polycystin- 2, a member of the TRP family of cation channels, cause autosomal dominant polycystic kidney disease, a disorder characterized by renal cysts and progressive renal failure. Polycystin- 2 functions as a calcium- permeable nonselective cation channel; however, it is disputed whether polycystin- 2 resides and acts at the plasma membrane or endoplasmic reticulum ( ER). We show that the subcellular localization and function of polycystin- 2 are directed by phosphofurin acidic cluster sorting protein ( PACS)- 1 and PACS- 2, two adaptor proteins that recognize an acidic cluster in the carboxy- terminal domain of polycystin- 2. Binding to these adaptor proteins is regulated by the phosphorylation of polycystin- 2 by the protein kinase casein kinase 2, required for the routing of polycystin- 2 between ER, Golgi and plasma membrane compartments. Our paradigm that polycystin- 2 is sorted to and active at both ER and plasma membrane reconciles the previously incongruent views of its localization and function. Furthermore, PACS proteins may represent a novel molecular mechanism for ion channel trafficking, directing acidic cluster- containing ion channels to distinct subcellular compartments.