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

Membrane environment imposes unique selection pressures on transmembrane domains of G protein-coupled receptors