Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7T...

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Main Authors:	Fatakia, Sarosh N., Costanzi, Stefano, Chow, Carson C.
Format:	Online
Language:	English
Published:	Public Library of Science 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221663/

id	pubmed-3221663
recordtype	oai_dc
spelling	pubmed-32216632011-11-30 Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors Fatakia, Sarosh N. Costanzi, Stefano Chow, Carson C. Research Article G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7TM) interhelical region, which had high mutual information with each other and many other positions in the 7TM. Here, we estimated the evolutionary selection pressure at those key positions. We found that the key positions of receptors for small molecule natural ligands were under strong negative selection. Receptors naturally activated by lipids had weaker negative selection in general when compared to small molecule-activated receptors. Selection pressure varied widely in peptide-activated receptors. We used this observation to predict that a subgroup of orphan GPCRs not under strong selection may not possess a natural small-molecule ligand. In the subgroup of MRGX1-type GPCRs, we identified a key position, along with two non-key positions, under statistically significant positive selection. Public Library of Science 2011-11-21 /pmc/articles/PMC3221663/ /pubmed/22132149 http://dx.doi.org/10.1371/journal.pone.0027813 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Fatakia, Sarosh N. Costanzi, Stefano Chow, Carson C.
spellingShingle	Fatakia, Sarosh N. Costanzi, Stefano Chow, Carson C. Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
author_facet	Fatakia, Sarosh N. Costanzi, Stefano Chow, Carson C.
author_sort	Fatakia, Sarosh N.
title	Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_short	Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_full	Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_fullStr	Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_full_unstemmed	Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_sort	molecular evolution of the transmembrane domains of g protein-coupled receptors
description	G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7TM) interhelical region, which had high mutual information with each other and many other positions in the 7TM. Here, we estimated the evolutionary selection pressure at those key positions. We found that the key positions of receptors for small molecule natural ligands were under strong negative selection. Receptors naturally activated by lipids had weaker negative selection in general when compared to small molecule-activated receptors. Selection pressure varied widely in peptide-activated receptors. We used this observation to predict that a subgroup of orphan GPCRs not under strong selection may not possess a natural small-molecule ligand. In the subgroup of MRGX1-type GPCRs, we identified a key position, along with two non-key positions, under statistically significant positive selection.
publisher	Public Library of Science
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221663/
_version_	1611489386394812416

Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors

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