Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo 255049, PR China.
Biochem Biophys Res Commun. 2011 Jul 1;410(2):159-63. doi: 10.1016/j.bbrc.2011.06.007. Epub 2011 Jun 7.
As mutations in the PRNP gene account for human hereditary prion diseases (PrDs), it is crucial to elucidating how these mutations affect the central pathogenic conformational transition of normal cellular prion protein (PrP(C)) to abnormal scrapie isoform (PrP(Sc)). Many studies proposed that these pathogenic mutations may make PrP more susceptible to conformational change through altering its structure stability. By evaluating the most recent observations regarding pathogenic mutations, it was found that the pathogenic mutations do not exert a uniform effect on the thermodynamic stability of the human PrP's structure. Through analyzing the reported PrDs-related mutations, we found that 25 out of 27 mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge. Based on the triggering role reported by previous studies of facilitating factors in PrP(C) conversion, e.g., lipid and polyanion, we proposed that the mutation-induced changes may strengthen the interaction between PrP and facilitating factors, which will accelerate PrP conversion and cause PrDs.
由于 PRNP 基因突变可导致人类遗传性朊病毒病（PrD），因此阐明这些突变如何影响正常细胞朊病毒蛋白（PrP(C)）向异常瘙痒型（PrP(Sc)）的中心致病性构象转变至关重要。许多研究表明，这些致病性突变可能通过改变其结构稳定性使 PrP 更容易发生构象变化。通过评估最近关于致病性突变的观察结果，发现致病性突变对人 PrP 结构的热力学稳定性没有产生统一的影响。通过分析报道的 PrD 相关突变，我们发现 27 个突变中有 25 个具有强烈的定向选择，即增强疏水性或降低负电荷并增加正电荷。基于先前研究中促进因子在 PrP(C)转化中触发作用的报道，例如脂质和多阴离子，我们提出突变诱导的变化可能会增强 PrP 与促进因子之间的相互作用，从而加速 PrP 转化并导致 PrD。
