論文

査読有り
2010年7月

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

BMC EVOLUTIONARY BIOLOGY
  • Madoka Koyanagi
  • ,
  • Julie A. Kerns
  • ,
  • Linda Chung
  • ,
  • Yan Zhang
  • ,
  • Scott Brown
  • ,
  • Tudor Moldoveanu
  • ,
  • Harmit S. Malik
  • ,
  • Mark Bix

10
開始ページ
223
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1186/1471-2148-10-223
出版者・発行元
BIOMED CENTRAL LTD

Background: 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.
Results: 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 IL4R alpha subunit shared by the Type I and Type II IL4 receptors. We show that this intraspecies variation affects the ability of IL4 neither to bind IL4 receptor alpha (IL4R alpha) nor to signal biological responses through its Type I receptor.
Conclusions: Our results - reminiscent of clustered positively selected sites revealing functionally important residues at host-virus interaction interfaces - are consistent with IL4 having evolved to avoid recurrent pathogen antagonism, while maintaining the capacity to bind and signal through its cognate receptor. This work exposes what may be a general feature of evolutionary conflicts fought by pathogen antagonists at host protein-protein interaction interfaces involved in immune signaling: the emergence of receptor-binding ligand epitopes capable of buffering amino acid variation.

Web of Science ® 被引用回数 : 12

リンク情報
DOI
https://doi.org/10.1186/1471-2148-10-223
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/20649995
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000282746400004&DestApp=WOS_CPL

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