The cellular prion protein binds copper in vivo
The cellular prion protein binds copper in vivo
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DOI：
10.1038/37783
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发表时间：
1997-12
期刊：
影响因子：
64.8
通讯作者：
David R. Brown;K. Qin;J. Herms;A. Madlung;J. Manson;R. Strome;P. Fraser;T. Kruck;A. Bohlen
中科院分区：
文献类型：
--
作者：
David R. Brown;K. Qin;J. Herms;A. Madlung;J. Manson;R. Strome;P. Fraser;T. Kruck;A. Bohlen
朊蛋白（PrPC）的正常细胞形式是致病性蛋白酶抗性形式（PrPSc）的前体，被认为会引起痒病、牛海绵状脑病（BSE）和克雅氏病。它的氨基末端包含八肽PHGGGWGQ，重复了四次，是哺乳动物PrPC保存最完好的区域之一。在这里，我们发现prpc的氨基末端结构域显示出5到6个结合铜（Cu(II)）的位点，以甘氨酸螯合物的形式呈现。在中性pH下，结合以正协同性发生，其结合亲和力与细胞外不稳定铜的估计相容。两种独立衍生的prpcgene -烧蚀（Prnp0/0）小鼠在富含膜的脑提取物中铜含量严重降低，在突触体和内核体富集的亚细胞部分中铜含量也有类似的降低。prnp0 /0小鼠的细胞表型也发生了改变，包括铜/锌超氧化物歧化酶活性的降低，以及过量铜存在时电生理反应的改变。这些发现表明，prpcc可以存在于体内的Cu-metalloprotein formin中。
The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt–Jakob disease. Its amino terminus contains the octapeptide PHGGGWGQ, which is repeated four times and is among the best-preserved regions of mammalian PrPC. Here we show that the amino-terminal domain of PrPCexhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate. At neutral pH, binding occurs with positive cooperativity, with binding affinity compatible with estimates for extracellular, labile copper. Two lines of independently derived PrPCgene-ablated (Prnp0/0) mice exhibit severe reductions in the copper content of membrane-enriched brain extracts and similar reductions in synaptosomal and endosome-enriched subcellular fractions.Prnp0/0mice also have altered cellular phenotypes, including a reduction in the activity of copper/zinc superoxide dismutase and altered electrophysiological responses in the presence of excess copper. These findings indicate that PrPCcan exist in a Cu-metalloprotein formin vivo.