Diversifying selection and functional analysis of interleukin-4 suggests antagonism-driven evolution at receptor-binding interfaces.

BMC Evolutionary Biology
Madoka KoyanagiMark Bix

Abstract

Interleukin-4 (IL4) is a secreted immunoregulatory cytokine critically involved in host protection from parasitic helminths 1. Reasoning that helminths may have evolved mechanisms to antagonize IL4 to maximize their dispersal, we explored mammalian IL4 evolution. This analysis revealed evidence of diversifying selection at 15 residues, clustered in epitopes responsible for IL4 binding to its Type I and Type II receptors. Such a striking signature of selective pressure suggested either recurrent episodes of pathogen antagonism or ligand/receptor co-evolution. To test the latter possibility, we performed detailed functional analysis of IL4 allotypes expressed by Mus musculus musculus and Mus musculus castaneus, which happen to differ at 5 residues (including three at positively selected sites) in and adjacent to the site 1 epitope that binds the IL4Ralpha subunit shared by the Type I and Type II IL4 receptors. We show that this intra-species variation affects the ability of IL4 neither to bind IL4 receptor alpha (IL4Ralpha) nor to signal biological responses through its Type I receptor. Our results - reminiscent of clustered positively selected sites revealing functionally important residues at host-virus interaction interfaces -...Continue Reading

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Citations

Nov 14, 2012·Annual Review of Genetics·Matthew D Daugherty, Harmit S Malik
Sep 15, 2012·Current Biology : CB·Thomas Boehm
Oct 19, 2017·Bioinformatics·Pengyuan LiHagit Shatkay
Jun 15, 2011·Growth Factors·Meenu R Pillai, Mark Bix
Sep 1, 2017·Genome Biology and Evolution·Matthew F BarberNels C Elde

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Methods Mentioned

BETA
chips
surface plasmon resonance
chip
PMA
biosensor
FACS

Software Mentioned

PhyML
BLASTN
PAL2NAL
TBLASTN
SBP
CLUSTAL
PyMOL Molecular Graphics System
BIAevaluation
HyPhy
Biacore

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