Abstract
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 TM domains evolve more slowly than do EM 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 TM 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.
Highlights
A protein’s evolution may be constrained by various functional or biophysical requirements
We have demonstrated that the average evolutionary rate ωof G protein-coupled receptors (GPCRs) TM domains is significantly less than that of EM domains, mirroring results of previous studies which have suggested this trend across several types of membrane proteins [Tourasse and Li, 2000, Julenius and Pedersen, 2006]
We found that the TM does evolve more slowly than does the EM, we emphasize that residues under positive selection were not uncommon across TM regions
Summary
A protein’s evolution may be constrained by various functional or biophysical requirements. Previous studies investigating the evolution of membrane proteins have focused primarily on average evolutionary rates, neither addressing rate heterogeneity nor site-based evolutionary parameters [Tourasse and Li, 2000, Gilad et al, 2000, Clark et al, 2003, Julenius and Pedersen, 2006].
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