Abstract
BackgroundThe availability of genome sequences, and inferred protein coding genes, has led to several proteome-wide studies of isoelectric points. Generally, isoelectric points are distributed following variations on a biomodal theme that originates from the predominant acid and base amino acid sidechain pKas. The relative populations of the peaks in such distributions may correlate with environment, either for a whole organism or for subcellular compartments. There is also a tendency for isoelectric points averaged over a subcellular location to not coincide with the local pH, which could be related to solubility. We now calculate the correlation of other pH-dependent properties, calculated from 3D structure, with subcellular pH.ResultsFor proteins with known structure and subcellular annotation, the predicted pH at which a protein is most stable, averaged over a location, gives a significantly better correlation with subcellular pH than does isoelectric point. This observation relates to the cumulative properties of proteins, since maximal stability for individual proteins follows the bimodal isoelectric point distribution. Histidine residue location underlies the correlation, a conclusion that is tested against a background of proteins randomised with respect to this feature, and for which the observed correlation drops substantially.ConclusionThere exists a constraint on protein pH-dependence, in relation to the local pH, that is manifested in the pKa distribution of histidine sub-proteomes. This is discussed in terms of protein stability, pH homeostasis, and fluctuations in proton concentration.
Highlights
The availability of genome sequences, and inferred protein coding genes, has led to several proteome-wide studies of isoelectric points
Results and Discussion pH-dependence of stability and subcellular pH A dataset of protein structures annotated by subcellular location was constructed as described in the Methods section (Figure 1)
We find that restrictions imposed by the composition of ionisable groups means that individual proteins have minima in pH-dependence, that tend to lie on either side of subcellular pH
Summary
The availability of genome sequences, and inferred protein coding genes, has led to several proteome-wide studies of isoelectric points. For the most part, pI distributions are not correlated with subcellular location or taxonomy [18] Amongst these varying conclusions, observations reinforced by multiple reports are that: individual protein pIs tend towards less extreme values for longer sequences, as a result of sampling statistics of acidic/basic amino acids [16,19]; subcellular proteome pIs may give net charge at environmental pH to mitigate against protein aggregation [18,20]; smaller proteomes tend to be more basic [15,16]. Processes suggested to underlie the trend include adaptation to environmental constraints, such as elevated host pH [15], and differences in the rate of accumulation of mutations (higher in intracellular organisms than free-living ones) [16]
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