Prion dimer is heterogenous and is modulated by multiple negative and positive motifs
Prion dimer is heterogenous and is modulated by multiple negative and positive motifs
复制标题
朊病毒二聚体是异质的，并受到多个负基序和正基序的调节
DOI：
10.1016/j.bbrc.2018.12.113
复制
发表时间：
2019-02-05
影响因子：
3.1
通讯作者：
Li, Chaoyang
中科院分区：
文献类型：
--
作者：
Gao, Zhenxing;Shi, Jing;Li, Chaoyang
正常朊病毒蛋白（PrP）转化为羊瘙痒病（PrPSc）的过程还不完全清楚。理论上，最小的PrP聚集体是二聚体。人PrP在位置179（C179）和214（C214）处含有两个半胱氨酸，使得能够形成二硫键。在这里，我们报告说，我们的重组人PrP（r-hPrP）制剂含有0.2-0.8%的二聚体，这是由一个或两个二硫键连接，连接C179-C179，C214-C214，或C179-C214。此外，二聚化受到多个基序的调节。虽然残基36-42抑制，但残基90-125和195-212促进二聚化。使36和42之间的单个残基突变增强二聚化，而使95-115内的带正电荷的残基或195-212内的带负电荷的残基突变防止二聚化。尽管整个八肽重复序列（5 OR）区域的缺失阻止了二聚化，但突变5 OR内的组氨酸增强了二聚化。此外，我们发现三分之二的遗传性朊病毒病患者的脑裂解物比对照组有更多的PrP二聚体。因此，PrP二聚化可能有助于朊病毒疾病。(C)2018爱思唯尔公司All rights reserved.
The conversion of the normal prion protein (PrP) into a scrapie priori (PrPSc) is incompletely understood. Theoretically, the smallest PrP aggregate is a dimer. Human PrP contains two cysteines at positions 179 (C179) and 214 (C214) enabling disulfide bonding. Here, we report that our recombinant human PrP (r-hPrP) preparations contain 0.2-0.8% dimer, which is linked by either one or two disulfide bonds, connected by C179-C179, C214-C214, or C179-C214. Furthermore, dimerization is regulated by multiple motifs. While residues 36-42 inhibit, residues 90-125, and 195-212 promote dimerization. Mutating individual residue between 36 and 42 enhances dimerization whereas mutating the positively charged residues within 95-115, or the negatively charged residues within 195-212 prevent dimerization. Although deletion of the entire octapeptide-repeat (5OR) region prevents dimerization, mutating the histidines within the 5OR enhances dimerization. In addition, we found that two out of three brain lysates from patients with inherited prion disease had more PrP dimers than controls. Thus, PrP dimerlzation may contribute to prion diseases. (C) 2018 Elsevier Inc. All rights reserved.