Pathogenic signal peptide variants in the human genome.
Pathogenic signal peptide variants in the human genome.
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DOI：
10.1093/nargab/lqad093
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发表时间：
2023-12
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
分泌蛋白和膜蛋白占所有细胞蛋白的三分之一，并含有N-末端信号肽，这些信号肽是蛋白靶向内质网（ER）所需的。信号肽的突变影响蛋白质的靶向、转运、加工和稳定性，并与人类疾病相关。然而，只有少数几个已经确定或定性。在这份报告中，我们使用生物信息学分析确定了人类基因组中的致病信号肽变体，并预测了其病理学的分子机制。我们恢复了超过65000个信号肽突变，超过11000个我们归类为致病性，并提出了区分其分子机制的框架。致病性突变影响超过3300个编码分泌和膜蛋白的基因。大多数致病性突变改变信号肽疏水核心，信号识别颗粒的关键识别区域，潜在地激活异常蛋白质产生调节（RAPP）质量控制和特异性mRNA降解。其余致病性变体（约25%）改变N-末端区域或信号肽酶加工位点，可导致ER膜易位缺陷或抑制蛋白质加工。这项工作为识别整个基因组的突变及其与人类疾病的联系提供了一个概念框架。
Secreted and membrane proteins represent a third of all cellular proteins and contain N-terminal signal peptides that are required for protein targeting to endoplasmic reticulum (ER). Mutations in signal peptides affect protein targeting, translocation, processing, and stability, and are associated with human diseases. However, only a few of them have been identified or characterized. In this report, we identified pathogenic signal peptide variants across the human genome using bioinformatic analyses and predicted the molecular mechanisms of their pathology. We recovered more than 65 thousand signal peptide mutations, over 11 thousand we classified as pathogenic, and proposed framework for distinction of their molecular mechanisms. The pathogenic mutations affect over 3.3 thousand genes coding for secreted and membrane proteins. Most pathogenic mutations alter the signal peptide hydrophobic core, a critical recognition region for the signal recognition particle, potentially activating the Regulation of Aberrant Protein Production (RAPP) quality control and specific mRNA degradation. The remaining pathogenic variants (about 25%) alter either the N-terminal region or signal peptidase processing site that can result in translocation deficiencies at the ER membrane or inhibit protein processing. This work provides a conceptual framework for the identification of mutations across the genome and their connection with human disease.
缺陷人类SRP诱导蛋白质质量控制，并触发压力反应。
影响因子：
5.6
作者：
Tikhonova, Elena B.;Guarnizo, Sneider Alexander Gutierrez;Kellogg, Morgana K.;Karamyshev, Alexander;Dozmorov, Igor M.;Karamysheva, Zemfira N.;Karamyshev, Andrey L.
通讯作者：
Karamyshev, Andrey L.
DOI：
10.1016/j.bbrc.2009.12.090
发表时间：
2010-01-15
影响因子：
3.1
作者：
Park, Soo-Young;Ye, Honggang;Steiner, Donald F.;Bell, Graeme I.
通讯作者：
Bell, Graeme I.
人apo-SRP72和SRP68/72复合物结构揭示了蛋白质易位的分子基础
影响因子：
5.5
作者：
Gao Y;Zhang Q;Lang Y;Liu Y;Dong X;Chen Z;Tian W;Tang J;Wu W;Tong Y;Chen Z
通讯作者：
Chen Z