Jarjanazi Hamdi, Savas Sevtap, Pabalan Noel, Dennis James W, Ozcelik Hilmi
Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Proteins. 2008 Feb 1;70(2):394-403. doi: 10.1002/prot.21548.
Proteins destined for secretion or membrane compartments possess signal peptides for insertion into the membrane. The signal peptide is therefore critical for localization and function of cell surface receptors and ligands that mediate cell-cell communication. About 4% of all human proteins listed in UniProt database have signal peptide domains in their N terminals. A comprehensive literature survey was performed to retrieve functional and disease associated genetic variants in the signal peptide domains of human proteins. In 21 human proteins we have identified 26 disease associated mutations within their signal peptide domains, 14 mutations of which have been experimentally shown to impair the signal peptide function and thus influence protein transportation. We took advantage of SignalP 3.0 predictions to characterize the signal peptide prediction score differences between the mutant and the wild-type alleles of each mutation, as well as 189 previously uncharacterized single nucleotide polymorphisms (SNPs) found to be located in the signal peptide domains of 165 human proteins. Comparisons of signal peptide prediction outcomes of mutations and SNPs, have implicated SNPs potentially impacting the signal peptide function, and thus the cellular localization of the human proteins. The majority of the top candidate proteins represented membrane and secreted proteins that are associated with molecular transport, cell signaling and cell to cell interaction processes of the cell. This is the first study that systematically characterizes genetic variation occurring in the signal peptides of all human proteins. This study represents a useful strategy for prioritization of SNPs occurring within the signal peptide domains of human proteins. Functional evaluation of candidates identified herein may reveal effects on major cellular processes including immune cell function, cell recognition and adhesion, and signal transduction.
destined for secretion or membrane compartments possess signal peptides for insertion into the membrane. The signal peptide is therefore critical for localization and function of cell surface receptors and ligands that mediate cell-cell communication. About 4% of all human proteins listed in UniProt database have signal peptide domains in their N terminals. A comprehensive literature survey was performed to retrieve functional and disease associated genetic variants in the signal peptide domains of human proteins. In 21 human proteins we have identified 26 disease associated mutations within their signal peptide domains, 14 mutations of which have been experimentally shown to impair the signal peptide function and thus influence protein transportation. We took advantage of SignalP 3.0 predictions to characterize the signal peptide prediction score differences between the mutant and the wild-type alleles of each mutation, as well as 189 previously uncharacterized single nucleotide polymorphisms (SNPs) found to be located in the signal peptide domains of 165 human proteins. Comparisons of signal peptide prediction outcomes of mutations and SNPs, have implicated SNPs potentially impacting the signal peptide function, and thus the cellular localization of the human proteins. The majority of the top candidate proteins represented membrane and secreted proteins that are associated with molecular transport, cell signaling and cell to cell interaction processes of the cell. This is the first study that systematically characterizes genetic variation occurring in the signal peptides of all human proteins. This study represents a useful strategy for prioritization of SNPs occurring within the signal peptide domains of human proteins. Functional evaluation of candidates identified herein may reveal effects on major cellular processes including immune cell function, cell recognition and adhesion, and signal transduction.
注定要分泌或进入膜区室的蛋白质具有用于插入膜中的信号肽。因此，信号肽对于介导细胞间通讯的细胞表面受体和配体的定位和功能至关重要。UniProt数据库中列出的所有人类蛋白质中约有4%在其N端具有信号肽结构域。进行了全面的文献调查，以检索人类蛋白质信号肽结构域中与功能和疾病相关的遗传变异。在21种人类蛋白质中，我们在其信号肽结构域中鉴定出26个与疾病相关的突变，其中14个突变已通过实验证明会损害信号肽功能，从而影响蛋白质运输。我们利用SignalP 3.0预测来表征每个突变的突变体和野生型等位基因之间的信号肽预测得分差异，以及在165种人类蛋白质的信号肽结构域中发现的189个先前未表征的单核苷酸多态性（SNP）。对突变和SNP的信号肽预测结果进行比较，表明SNP可能会影响信号肽功能，进而影响人类蛋白质的细胞定位。大多数顶级候选蛋白质代表与细胞的分子运输、细胞信号传导和细胞间相互作用过程相关的膜蛋白和分泌蛋白。这是第一项系统地表征所有人类蛋白质信号肽中发生的遗传变异的研究。这项研究代表了一种用于对人类蛋白质信号肽结构域中发生的SNP进行优先级排序的有用策略。对本文鉴定的候选物进行功能评估可能会揭示其对包括免疫细胞功能、细胞识别和粘附以及信号转导在内的主要细胞过程的影响。
