The prion-ZIP connection: From cousins to partners in iron uptake.
The prion-ZIP connection: From cousins to partners in iron uptake.
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DOI：
10.1080/19336896.2015.1118602
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发表时间：
2015
期刊：
影响因子：
2.3
通讯作者：
Tripathi AK
中科院分区：
文献类型：
--
作者：
Singh N;Asthana A;Baksi S;Desai V;Haldar S;Hari S;Tripathi AK
来自不同研究方向的一致观察结果开始阐明散发性克雅氏病（sCJD）脑铁平衡失调的原因，这是一种神经退行性疾病，与朊蛋白（PrPC）（一种质膜糖蛋白）从α-螺旋型转化为富含β-片的PrP-scrapie （PrPSc）亚型有关。生化证据表明，PrPC通过膜结合铁还原酶（FR）促进细胞铁摄取，FR是铁通过金属转运体跨生物膜运输所必需的活性。一个完全不同的实验方法揭示了PrPC和Zrt之间的进化联系，irt样蛋白（ZIP）家族，一组蛋白质参与锌，铁和锰在质膜上的运输。PrPC与某些ZIP家族成员在质膜上的物理接近，以及共表达PrPC和ZIP14的细胞对细胞外铁的摄取增加，表明PrPC作为该家族某些成员的FR伴侣起作用。因此，PrPC和ZIP蛋白之间的联系超越了共同的祖先，延伸到功能合作。在这里，我们总结了支持PrPC在细胞铁摄取中的促进作用的证据，以及这种活性对sCJD大脑铁代谢的影响。
Converging observations from disparate lines of inquiry are beginning to clarify the cause of brain iron dyshomeostasis in sporadic Creutzfeldt-Jakob disease (sCJD), a neurodegenerative condition associated with the conversion of prion protein (PrPC), a plasma membrane glycoprotein, from α-helical to a β-sheet rich PrP-scrapie (PrPSc) isoform. Biochemical evidence indicates that PrPC facilitates cellular iron uptake by functioning as a membrane-bound ferrireductase (FR), an activity necessary for the transport of iron across biological membranes through metal transporters. An entirely different experimental approach reveals an evolutionary link between PrPC and the Zrt, Irt-like protein (ZIP) family, a group of proteins involved in the transport of zinc, iron, and manganese across the plasma membrane. Close physical proximity of PrPC with certain members of the ZIP family on the plasma membrane and increased uptake of extracellular iron by cells that co-express PrPC and ZIP14 suggest that PrPC functions as a FR partner for certain members of this family. The connection between PrPC and ZIP proteins therefore extends beyond common ancestry to that of functional cooperation. Here, we summarize evidence supporting the facilitative role of PrPC in cellular iron uptake, and implications of this activity on iron metabolism in sCJD brains.