Marginal protein stability drives subcellular proteome isoelectric point

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• A positive correlation exists between subcellular compartment pH and the median isoelectric point (pI) of associated proteomes.
• Proteins in acidic compartments like lysosomes have lower median pIs, while those in basic compartments like mitochondria have higher median pIs.

Purpose of the Study:

• To investigate the mechanisms underlying the correlation between subcellular pH and proteome median pI.
• To determine if this correlation is driven by functional adaptation or other evolutionary processes.

Main Methods:

• Development of a protein model incorporating residue burial upon folding.
• Analysis of evolutionary processes, including neutral evolution and functional selection.

Main Results:

• A protein model considering residue burial successfully recapitulated the observed correlation between proteome pI and environmental pH.
• The correlation can be fully explained by neutral evolution, without invoking functional selection.
• Acidic environments favor burying acidic residues, leading to accumulation, while alkaline environments favor burying basic residues.

Conclusions:

• The pI distributions of subcellular proteomes are likely a consequence of molecular spandrels arising from marginal stability, rather than direct functional adaptations to pH.
• Neutral evolution and the biophysical constraints of residue burial play a significant role in shaping proteome characteristics.