BACKGROUND Whole-proteome distributions of protein isoelectric point (pI) values in different organisms are bi- or trimodal with some variations. It was suggested that the observed multimodality of the proteome-wide pI distributions is associated with subcellular localization-specific differences in the local pI distributions. However, the factors responsible for variation of the intracellular localization-specific pI profiles have not been investigated in detail. RESULTS In this work, we explored proteome-wide pI distributions of 32,138 human proteins predicted to reside in 10 subcellular compartments, as well as the pI distributions of experimentally observed lysosomal and Golgi proteins. The distributions were found to differ significantly, although all of them adhered to the major recurrent bimodal pattern. Grossly, acid-biased and alkaline-biased patterns with various minor statistical features were observed at different subcellular locations. Bioinformatics analysis revealed the existence of strong statistically significant correlations between protein pI and subcellular localization. Most markedly, protein pI was found to correlate positively with nuclear and mitochondrial locations and negatively with cytoskeletal, cytoplasmic, lysosomal and peroxisomal environment. Further analysis demonstrated that subcellular compartment-specific pI distributions are greatly influenced by local pH and organelle membrane charge. Multiple nonlinear regression analysis identified a polynomial function of the two variables that best fitted the mean pI values of the localization-specific pI distributions. A high coefficient of determination calculated for this regression (R2 = 0.98) suggests that local pH and organelle membrane charge are the major factors responsible for variation of the intracellular localization-specific pI profiles. CONCLUSIONS Our study demonstrates that strong correlations exist between protein pI and subcellular localization. The specific pI distributions at different subcellular locations are defined by local environment. Predominantly, it is the local pH and membrane charge that shape the organelle-specific protein pI patterns. These findings expand our understanding of spatial organization of the human proteome.

中文翻译：

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蛋白pI在人蛋白质组中的定位特异性分布受局部pH和膜电荷的支配。

背景技术不同生物体中蛋白质等电点（pI）值的全蛋白质组分布是双峰或三峰的，且存在一些差异。有人认为，蛋白质组范围的pI分布的观察到的多态性与局部pI分布中的亚细胞定位特异性差异有关。但是，尚未详细研究引起细胞内定位特异性pI谱变化的因素。结果在这项工作中，我们探索了预计在10个亚细胞区室中驻留的32,138种人类蛋白质的蛋白质组范围的pI分布，以及实验观察到的溶酶体和高尔基体蛋白的pI分布。尽管所有分布都遵循主要的经常性双峰模式，但发现分布有显着差异。总的来说，在不同的亚细胞位置观察到具有各种次要统计特征的酸偏和碱偏模式。生物信息学分析表明，蛋白质pI与亚细胞定位之间存在很强的统计学显着相关性。最明显的是，发现蛋白pI与核和线粒体位置呈正相关，与细胞骨架，细胞质，溶酶体和过氧化物酶体环境呈负相关。进一步的分析表明，亚细胞区室特异性pI分布受局部pH和细胞器膜电荷的影响很大。多元非线性回归分析确定了两个变量的多项式函数，这些函数最适合于特定于本地化的pI分布的平均pI值。计算得出的高确定性系数（R2 = 0.98）表明，局部pH和细胞器膜电荷是造成细胞内定位特异性pI图谱变化的主要因素。结论我们的研究表明，蛋白pI与亚细胞定位之间存在很强的相关性。不同亚细胞位置的特定pI分布由局部环境定义。主要是局部pH和膜电荷决定了细胞器特异性蛋白pI模式。这些发现扩大了我们对人类蛋白质组空间组织的理解。结论我们的研究表明，蛋白pI与亚细胞定位之间存在很强的相关性。不同亚细胞位置的特定pI分布由局部环境定义。主要是局部pH和膜电荷决定了细胞器特异的蛋白质pI模式。这些发现扩大了我们对人类蛋白质组空间组织的理解。结论我们的研究表明，蛋白pI与亚细胞定位之间存在很强的相关性。不同亚细胞位置的特定pI分布由局部环境定义。主要是局部pH和膜电荷决定了细胞器特异的蛋白质pI模式。这些发现扩大了我们对人类蛋白质组空间组织的理解。