Membrane proteins exist in distinctly different environments than do soluble proteins, resulting in differences between their respective biophysical and evolutionary properties. In comparison with soluble proteins, relatively little is known about how the unique biophysical properties of membrane proteins affect their evolutionary properties at the residue level. In particular, transmembrane (TM) regions of membrane proteins tend to be more conserved than regions outside of the membrane (extramembrane [EM] regions), but the mechanisms underlying this phenomenon are not well understood. Here, we combine homology-based high-resolution three-dimensional protein models with rigorous evolutionary rate calculations to quantitatively assess residue-level structure-evolution relationships in the yeast membrane proteome. We find that residue evolutionary rate increases linearly with decreasing residue burial, regardless of the hydrophobic or hydrophilic nature of the solvent environment. This finding supports a direct relationship between a residue's selective constraint and the extent of its packing interactions with neighboring residues, independent of hydrophobic effects. Most importantly, for a fixed degree of burial, residues from TM regions tend to evolve more slowly than residues from EM regions. We attribute this difference to the increased importance of packing constraints and the decreased importance of hydrophobic effects in TM regions. This additional selective constraint on TM residues plays a dominant role in explaining why TM regions evolve more slowly than EM regions. In addition to revealing the universality of the linear relationship between residue burial and selective constraint across solvent environments, our work highlights the distinct residue-level evolutionary consequences imposed by the unique biophysical properties of the membrane environment.
|Evidence ID||Analyze ID||Interactor||Interactor Systematic Name||Interactor||Interactor Systematic Name||Type||Assay||Annotation||Action||Modification||Phenotype||Source||Reference||Note|
|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Gene Ontology Term||Gene Ontology Term ID||Qualifier||Aspect||Method||Evidence||Source||Assigned On||Reference||Annotation Extension|
|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Phenotype||Experiment Type||Experiment Type Category||Mutant Information||Strain Background||Chemical||Details||Reference|
|Evidence ID||Analyze ID||Regulator||Regulator Systematic Name||Target||Target Systematic Name||Experiment||Conditions||Strain||Source||Reference|