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

TL;DR

This study reveals that the membrane environment uniquely influences the evolution of GPCR transmembrane domains, which evolve more slowly yet exhibit high variability and positive selection, driven by biophysical constraints and functional needs.

Contribution

It provides the first detailed analysis of site-specific evolutionary rates in GPCR transmembrane versus extramembrane regions, highlighting the impact of membrane constraints on evolution.

Findings

Transmembrane domains evolve more slowly than extramembrane domains.

Many GPCRs show positive selection at both TM and EM residues.

Chemosensory GPCRs evolve faster, especially in TM regions.

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 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.