Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

Kelsey J Metzger,Michael A Thomas

doi:10.1186/1471-2148-10-139

Kelsey J Metzger, Michael A Thomas

Open Access

https://doi.org/10.1186/1471-2148-10-139

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Abstract

BackgroundCC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions.In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events.Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML) were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (CCR) gene family. The results of neutral vs. adaptive evolution (positive selection) hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω) >1.ResultsOf the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only CCR2 and CCR3 contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive selection code for amino acid residues located in extracellular domains of the receptor protein products.ConclusionsThese results suggest that amino acid residues present in intracellular and membrane-bound domains are more selectively constrained for functional signal transduction and homo- or heterodimerization, whereas amino acid residues in extracellular domains of these receptor proteins evolve more quickly, perhaps due to heightened selective pressure resulting from ligand-binding and pathogen interactions of extracellular domains.

Highlights

CC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells
These results suggest that amino acid residues present in intracellular and membrane-bound domains are more selectively constrained for functional signal transduction and homo- or heterodimerization, whereas amino acid residues in extracellular domains of these receptor proteins evolve more quickly, perhaps due to heightened selective pressure resulting from ligand-binding and pathogen interactions of extracellular domains
The analysis for CCR2 had a total of 380 amino acid sites, and nine amino acid sites were identified as sites of positive selection (Table 2) using Bayes empirical Bayes (BEB) analysis [35]

Summary

Introduction

CC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. Chemokines, in conjunction with adhesion molecules, recruit specific subpopulations of leukocytes by activating various receptors and initiating signaling through G protein-coupled pathways [8,9]. Nucleotide mutations in the open reading frame coding for chemokine receptors can have a dramatic effect on receptor activity or little effect, depending on the location of the substitution and the nature of the amino acid replacement: amino acid substitutions resulting in alterations at key ligand binding extracellular domains or intracellular G-protein coupled domains in particular are known to result in disrupted or abnormal receptor activity [4]. Mutations in the regulatory nucleotide sequence of chemokine receptors can result in changes in gene expression and subsequent protein activity [17,18]

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