Abstract
BackgroundWhole-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.ResultsIn 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.ConclusionsOur 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.
Highlights
Whole-proteome distributions of protein isoelectric point values in different organisms are bi- or trimodal with some variations
It was further found that cytosolic and integral membrane proteins have pI distributions corresponding to the two observed modes; cytoplasmic proteins exhibited a distinct clustering at pI 5.0 to 6.0, and integral membrane proteins clustered at around pI 8.5 to 9.0 [8]
The peaks are not Gaussian, and the distribution, as a whole, displays a number of minor statistical features, such as peak shoulders, sub-peaks and minor peaks. These features are further scrutinized in the “Distribution profiling” section
Summary
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. Subsequent whole-proteome studies demonstrated that the pI distributions of eukaryotic proteins are generally trimodal. Nuclear proteins were found to have a broad distribution encompassing the range from pI 4.5 to 10.0 that may account for the third mode found in eukaryotes [8]. For instance, a minor peak at around pI = 11.5, were observed in the proteome-wide pI distributions [10, 11], further suggesting the existence of distinct subcellular localization-specific protein pI profiles
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