  We have investigated the influence of the plasma membrane environment on the
molecular evolution of G protein-coupled receptors (GPCRs), the largest
receptor family in Metazoa. In particular, we have analyzed the site-specific
rate variation across the two primary structural partitions, transmembrane (TM)
and extramembrane (EM), of these membrane proteins. We find that transmembrane
domains evolve more slowly than do extramembrane domains, though TM domains
display increased rate heterogeneity relative to their EM counterparts.
Although the majority of residues across GPCRs experience strong to weak
purifying selection, many GPCRs experience positive selection at both TM and EM
residues, albeit with a slight bias towards the EM. Further, a subset of GPCRs,
chemosensory receptors (including olfactory and taste receptors), exhibit
increased rates of evolution relative to other GPCRs, an effect which is more
pronounced in their TM spans. Although it has been previously suggested that
the TM's low evolutionary rate is caused by their high percentage of buried
residues, we show that their attenuated rate seems to stem from the strong
biophysical constraints of the membrane itself, or by functional requirements.
In spite of the strong evolutionary constraints acting on the transmembrane
spans of GPCRs, positive selection and high levels of evolutionary rate
variability are common. Thus, biophysical constraints should not be presumed to
preclude a protein's ability to evolve.
