Sulfated glycans and elevated temperature stimulate PrPSc-dependent cell-free formation of protease-resistant prion protein
Sulfated glycans and elevated temperature stimulate PrPSc-dependent cell-free formation of protease-resistant prion protein
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DOI：
10.1093/emboj/20.3.377
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发表时间：
2001-02-01
期刊：
影响因子：
11.4
通讯作者：
Caughey, B
中科院分区：
文献类型：
--
作者：
Wong, C;Xiong, LW;Caughey, B
在传染性海绵状脑病(TSE)中，通常认为需要将正常的、对蛋白酶敏感的普里恩蛋白(PrP-sen或PrPC)构象转换为对蛋白酶敏感的形式(PrP-RES或PrPSc)，内源性硫酸糖胺聚糖与PrP-RES在体内的沉积有关，这表明它们可能促进PrP-RES的形成。另一方面，某些外源性硫酸葡聚糖在体内可以显著抑制PrP-res的蓄积，并作为预防性的抗TSE化合物。为了研究硫酸多糖对PrP-RES形成的看似矛盾的影响，我们在生理相容的无细胞条件下测试了它们对PrP转化的直接影响。硫酸乙酰肝素和多硫酸戊聚糖促进PrP-RES的形成。温度升高进一步刺激了转化率。高温和多硫酸戊聚糖都促进了种间PrP的转化。圆二色光谱测量表明，多硫酸戊聚糖诱导了PrP-sen的构象变化，这可能增强了PrP-RES诱导的转化。这些结果表明，某些硫酸化的糖胺聚糖可以直接影响PrP的转化反应。因此，根据情况的不同，硫酸多糖可能是这一明显致病过程的辅助因子或抑制剂。
A conformational conversion of the normal, protease-sensitive prion protein (PrP-sen or PrPC) to a protease-resistant form (PrP-res or PrPSc) is commonly thought to be required in transmissible spongiform encephalopathies (TSEs), Endogenous sulfated glycosaminoglycans are associated with PrP-res deposits in vivo, suggesting that they may facilitate PrP-res formation. On the other hand, certain exogenous sulfated glycans can profoundly inhibit PrP-res accumulation and serve as prophylactic anti-TSE compounds in vivo. To investigate the seemingly paradoxical effects of sulfated glycans on PrP-res formation, we have assayed their direct effects on PrP conversion under physiologically compatible cell-free conditions. Heparan sulfate and pentosan polysulfate stimulated PrP-res formation. Conversion was stimulated further by increased temperature. Both elevated temperature and pentosan polysulfate promoted interspecies PrP conversion. Circular dichroism spectropolarimetry measurements showed that pentosan polysulfate induced a conformational change in PrP-sen that may potentiate its PrP-res-induced conversion. These results show that certain sulfated glycosaminoglycans can directly affect the PrP conversion reaction. Therefore, depending upon the circumstances, sulfated glycans may be either cofactors or inhibitors of this apparently pathogenic process.