Journal of Molecular Evolution

, Volume 76, Issue 3, pp 172–182 | Cite as

Membrane Environment Imposes Unique Selection Pressures on Transmembrane Domains of G Protein-Coupled Receptors

  • Stephanie J. Spielman
  • Claus O. Wilke


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.


Protein evolution G protein-coupled receptors Membrane proteins Positive selection 



This work was supported by NIH grant R01 GM088344 to C.O.W. We thank Austin G. Meyer for his thoughtful comments.

Supplementary material

239_2012_9538_MOESM1_ESM.rtf (4 kb)
Supplementary material 1 (RTF 5 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.The University of Texas at AustinAustinUSA

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