BACKGROUND Impaired proteostatic regulation of proteins with prion-like domains (PrLDs) is associated with a variety of human diseases including neurodegenerative disorders, myopathies, and certain forms of cancer. For many of these disorders, current models suggest a prion-like molecular mechanism of disease, whereby proteins aggregate and spread to neighboring cells in an infectious manner. The development of prion prediction algorithms has facilitated the large-scale identification of PrLDs among "reference" proteomes for various organisms. However, the degree to which intraspecies protein sequence diversity influences predicted prion propensity has not been systematically examined. RESULTS Here, we explore protein sequence variation introduced at genetic, post-transcriptional, and post-translational levels, and its influence on predicted aggregation propensity for human PrLDs. We find that sequence variation is relatively common among PrLDs and in some cases can result in relatively large differences in predicted prion propensity. Sequence variation introduced at the post-transcriptional level (via alternative splicing) also commonly affects predicted aggregation propensity, often by direct inclusion or exclusion of a PrLD. Finally, analysis of a database of sequence variants associated with human disease reveals a number of mutations within PrLDs that are predicted to increase prion propensity. CONCLUSIONS Our analyses expand the list of candidate human PrLDs, quantitatively estimate the effects of sequence variation on the aggregation propensity of PrLDs, and suggest the involvement of prion-like mechanisms in additional human diseases.

中文翻译：

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天然和致病性蛋白质序列变异会影响人类蛋白质组内部和整个蛋白质组中的ion病毒样结构域。

背景技术具有病毒样结构域（PrLDs）的蛋白的蛋白质调节能力受损与多种人类疾病相关，包括神经退行性疾病，肌病和某些形式的癌症。对于这些疾病中的许多疾病，当前的模型提示疾病的病毒样分子机制，从而蛋白质以感染性方式聚集并扩散到邻近细胞。ion病毒预测算法的发展促进了对各种生物的“参考”蛋白质组中的PrLD的大规模鉴定。但是，种内蛋白质序列多样性影响预测的ion病毒倾向的程度尚未得到系统地研究。结果在这里，我们探讨了在遗传，转录后和翻译后水平引入的蛋白质序列变异，及其对人类PrLD预测聚集倾向的影响。我们发现，序列变异在PrLD之间相对普遍，在某些情况下可能导致预测的ion病毒倾向存在较大差异。在转录后水平上引入的序列变异（通过替代剪接）通常也通过直接包含或排除PrLD来影响预测的聚集倾向。最后，对与人类疾病相关的序列变异数据库的分析揭示了PrLD中的许多突变，这些突变预计会增加increase病毒的倾向。结论我们的分析扩大了候选人类PrLDs的范围，定量估计了序列变异对PrLDs聚集倾向的影响，并暗示了ion病毒样机制参与了其他人类疾病。