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Marginal protein stability drives subcellular proteome isoelectric point

Significance The rules of protein design are often derived from analyzing the properties of natural proteins. However, unlike designed proteins, natural proteins are the product of long evolutionary histories, confounding efforts to identify which properties are directly related to function versus those that are a by-product of the evolutionary process. We critically examine the observation that the isoelectric point—the pH at which proteins have no net charge—correlates with the pH of the subcellular environment occupied by that protein. This correlation is not due to adaptive selection, but is a by-product of neutral evolution. This insight can be used to understand the evolution of proteins at a range of pH and design molecules for such environments. There exists a positive correlation between the pH of subcellular compartments and the median isoelectric point (pI) for the associated proteomes. Proteins in the human lysosome—a highly acidic compartment in the cell—have a median pI of ∼6.5, whereas proteins in the more basic mitochondria have a median pI of ∼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 pI 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 pI distributions of subcellular proteomes are likely not a direct result of functional adaptations to pH, but a molecular spandrel stemming from marginal stability.