Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 46, Pages 11778-11783Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1809098115
Keywords
molecular spandrels; neutral evolution; protein folding; acid-base equilibria
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Funding
- National Institutes of Health [DP2 OD-006478]
- National Aeronautics and Space Administration [80NSSC18M0093]
- Rutgers University Bernstein Fellowship
- Rutgers University Aresty Undergraduate Research Fellowship
- CABM SURE program
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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.
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