Marginal protein stability drives subcellular proteome isoelectric point

There exists a positive correlation between the pH of subcellular compartments and the median isoelectric point (pl) for the associated proteomes. Proteins in the human lysosome-a highly acidic compartment in the cell-have a median pl of similar to 6.5, whereas proteins in the more basic mitochondria have a median pl of similar to 8.0. Proposed mechanisms reflect potential adaptations to pH. For example, enzyme active site general acid/base residue pKs are likely evolved to match environmental pH. However, such effects would be limited to a few residues on specific proteins, and might not affect the proteome at large. A protein model that considers residue burial upon folding recapitulates the correlation between proteome pl and environmental pH. This correlation can be fully described by a neutral evolution process; no functional selection is included in the model. Proteins in acidic environments incur a lower energetic penalty for burying acidic residues than basic residues, resulting in a net accumulation of acidic residues in the protein core. The inverse is true under alkaline conditions. The pl distributions of subcellular proteomes are likely not a direct result of functional adaptations to pH, but a molecular spandrel stemming from marginal stability.