Na+/K+-ATPase is present in scrapie-associated fibrils, modulates PrP misfolding in vitro and links PrP function and dysfunction.
Na+/K+-ATPase is present in scrapie-associated fibrils, modulates PrP misfolding in vitro and links PrP function and dysfunction.
复制标题
Na+/K+-ATP 酶存在于痒病相关原纤维中，在体外调节 PrP 错误折叠，并将 PrP 功能和功能障碍联系起来。
DOI：
10.1371/journal.pone.0026813
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Gill AC
中科院分区：
文献类型：
--
作者：
Graham JF;Kurian D;Agarwal S;Toovey L;Hunt L;Kirby L;Pinheiro TJ;Banner SJ;Gill AC
传染性海绵状脑病的特征在于朊病毒蛋白的纤维状和/或斑块状形式的广泛沉积。这些聚集形式是由正常朊病毒蛋白PrPC错误折叠为疾病相关形式PrPSc产生的，其机制仍然难以捉摸，但需要PrPC和PrPSc同种型之间的直接或间接相互作用。大量证据表明其他非PrP分子是错误折叠过程的积极参与者，催化和指导PrPC的构象转化或提供确保PrPC和PrPSc在转化过程中正确对齐的支架。此类分子可能对不同的瘙痒症菌株具有特异性，以促进差异性朊病毒蛋白错误折叠。由于分子辅因子可能成为整合到不断增长的蛋白原纤维在朊病毒转换，我们已经调查了朊病毒疾病特异性存款的蛋白质鸟枪蛋白质组学羊瘙痒症相关的原纤维（SAF）从感染3种不同的小鼠传代羊瘙痒症菌株的小鼠。同时使用阴性对照制备物使我们能够鉴定和区分通过SAF分离方案非特异性富集的蛋白质。我们发现了几种蛋白质，共纯化，特别是与SAF从感染的大脑，但这些都是可重复的，并证明特定的瘙痒症菌株。Na+/K+-ATP酶的α链是所有3种菌株的SAF共有的，我们测试了该蛋白调节重组PrP体外错误折叠的能力。Na+/K+-ATP酶增强了重组PrP的疾病特异性转化效率，这表明它可能作为一种分子辅助因子。与先前的结果一致，相同的蛋白质抑制重组PrP的fiflensation动力学。由于PrPC和Na+/K+-ATP酶之间的功能相互作用先前已在星形胶质细胞中报道，我们的数据突出了该分子作为PrP功能，功能障碍和错误折叠之间的关键联系。
Transmissible spongiform encephalopathies are characterised by widespread deposition of fibrillar and/or plaque-like forms of the prion protein. These aggregated forms are produced by misfolding of the normal prion protein, PrPC, to the disease-associated form, PrPSc, through mechanisms that remain elusive but which require either direct or indirect interaction between PrPC and PrPSc isoforms. A wealth of evidence implicates other non-PrP molecules as active participants in the misfolding process, to catalyse and direct the conformational conversion of PrPC or to provide a scaffold ensuring correct alignment of PrPC and PrPSc during conversion. Such molecules may be specific to different scrapie strains to facilitate differential prion protein misfolding. Since molecular cofactors may become integrated into the growing protein fibril during prion conversion, we have investigated the proteins contained in prion disease-specific deposits by shotgun proteomics of scrapie-associated fibrils (SAF) from mice infected with 3 different strains of mouse-passaged scrapie. Concomitant use of negative control preparations allowed us to identify and discount proteins that are enriched non-specifically by the SAF isolation protocol. We found several proteins that co-purified specifically with SAF from infected brains but none of these were reproducibly and demonstrably specific for particular scrapie strains. The α-chain of Na+/K+-ATPase was common to SAF from all 3 strains and we tested the ability of this protein to modulate in vitro misfolding of recombinant PrP. Na+/K+-ATPase enhanced the efficiency of disease-specific conversion of recombinant PrP suggesting that it may act as a molecular cofactor. Consistent with previous results, the same protein inhibited fibrillisation kinetics of recombinant PrP. Since functional interactions between PrPC and Na+/K+-ATPase have previously been reported in astrocytes, our data highlight this molecule as a key link between PrP function, dysfunction and misfolding.
登录
查看更多内容
DOI：
10.1006/bbrc.1996.0211
发表时间：
1996-02-06
影响因子：
3.1
作者：
Baumann, MH;Wisniewski, T;Ghiso, J
通讯作者：
Ghiso, J
影响因子：
3.7
作者：
Dumpitak, C;Beekes, M;Riesner, D
通讯作者：
Riesner, D
影响因子：
16.6
作者：
Goold, R.;Rabbanian, S.;Sutton, L.;Andre, R.;Arora, P.;Moonga, J.;Clarke, A. R.;Schiavo, G.;Jat, P.;Collinge, J.;Tabrizi, S. J.
通讯作者：
Tabrizi, S. J.
影响因子：
4.1
作者：
Brown, DR;Wong, BS;Jones, IM
通讯作者：
Jones, IM
影响因子：
4.7
作者：
Bergemalm, Daniel;Forsberg, Karin;Marklund, Stefan L.
通讯作者：
Marklund, Stefan L.