The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells
The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells
复制标题
DOI：
10.1038/nm1297-1383
复制
发表时间：
1997-12-01
期刊：
影响因子：
82.9
通讯作者：
Weiss, S
中科院分区：
文献类型：
--
作者：
Rieger, R;Edenhofer, F;Weiss, S
朊病毒被认为是由引起传染性海绵状脑病的传染性蛋白组成的。根据压倒性的证据，致病性朊病毒蛋白PrPSc将其宿主编码的同种异构体PrPc转化为不溶性PrPSc聚集体，并伴有病理修饰（回顾，见参考文献）。1 - 3)。尽管人们对PrPc的生理作用知之甚少(4)，但对PrP敲除小鼠的研究表明，PrPc是朊病毒疾病发生所必需的。利用酵母双杂交技术，在酿酒酵母中鉴定出37 kda的层粘连蛋白受体前体（LRP）与细胞朊蛋白PrPc相互作用。对酿酒酵母LRP-PrP相互作用位点的定位分析表明，PrP和层粘连蛋白在LRP上具有相同的结合结构域（氨基酸161 ~ 180）(6)。在昆虫（Sf9）和哺乳动物细胞（COS-7）中证实了LRP-PrP的相互作用。瘙痒病感染小鼠N(2)a细胞及小鼠脑、脾中LRP水平升高。相比之下，感染牛海绵状脑病剂（BSE）的小鼠的这些器官中的LRP浓度没有显著改变，它们的PrPSc积累量较低。然而，感染痒病的仓鼠的LRP水平在大脑和胰腺中显著增加，在脾脏中略有增加，而在肝脏中没有改变。这些数据表明，LRP浓度的增加与小鼠和仓鼠器官中PrPSc的积累有关。层粘连蛋白受体前体在哺乳动物中高度保守，位于细胞表面，可能在哺乳动物细胞中作为朊蛋白的受体或辅助受体。
Prions are thought to consist of infectious proteins that cause transmissible spongiform encephalopathies'. According to overwhelming evidence, the pathogenic prion protein PrPSc converts its host encoded isoform PrPc into insoluble aggregates of PrPSc, concomitant with pathological modifications (for review, see refs. 1-3). Although the physiological role of PrPc is poorly understood(4), studies with PrP knockout mice demonstrated that PrPc is required for the development of prion diseases'. Using the yeast two-hybrid technology in Saccharomyces cerevisiae, we identified the 37-kDa laminin receptor precursor (LRP) as interacting with the cellular prion protein PrPc. Mapping analysis of the LRP-PrP interaction site in S. cerevisiae revealed that PrP and laminin share the same binding domain (amino acids 161 to 180)(6) on LRP. The LRP-PrP interaction was confirmed in vivo in insect (Sf9) and mammalian cells (COS-7). The LRP level was increased in scrapie-infected murine N(2)a cells and in brain and spleen of scrapie-infected mice. In contrast, the LRP concentration was not significantly altered in these organs from mice infected with the bovine spongiform encephalopathic agent (BSE), which have a lower PrPSc accumulation. LRP levels, however, were dramatically increased in brain and pancreas, slightly increased in the spleen and not altered in the liver of scrapie-infected hamsters. These data show that enhanced LRP concentrations are correlated with PrPSc accumulation in organs from mice and hamsters. The laminin receptor precursor, which is highly conserved among mammals and is located on the cell surface, may act as a receptor or coreceptor for the prion protein on mammalian cells.