Analysis of Fish IL-1ß and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design

A. I. Koussounnadis, David William Ritchie, G. J. L. Kemp, Christopher John Secombes

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

A large number of IL-1 protein sequences have become available recently from a range of vertebrate species and especially from bony fish. However, 3D structures are still only known for mammalian IL-1. In this review, we use a multiple sequence alignment of all published non-mammalian vertebrate IL-1beta proteins to locate the structurally important residues critical for maintaining the beta-trefoil fold and we investigate the degree to which functionally important residues involved in receptor binding are conserved across vertebrate species. We find that although there is a high level of variability of positions involved in receptor binding, the mode of binding and overall shape of the ligand-receptor complex is probably maintained. This implies that each species has evolved its own unique interleukin-1 signalling system through ligand-receptor co-cvolution. Nonetheless, the IL-1beta processing mechanism in non-mammalian vertebrates remains unclear because, with the exception of three bony fish, all non-mammalian IL-1beta sequences discovered so far lack an ICE (Interleukin Converting Enzyme) cut site. The IL-1 system has become an important drug target because of its significance in inflammatory diseases. Research on peptides derived from IL-1beta has identified peptides that possess agonist activity in humans and in trout, and peptides with antagonist activity. The agonist peptides map to two distinct loop regions of IL-1beta that are known to interact with the flexible domain III of the corresponding receptor. Further analysis of the IL-1 system may prove useful in engineering IL-1 with improved features and in suggesting new avenues for therapeutic intervention.

Original languageEnglish
Pages (from-to)3857-3871
Number of pages14
JournalCurrent Pharmaceutical Design
Volume10
Issue number31
DOIs
Publication statusPublished - Dec 2004

Keywords

  • Interleukin-1
  • beta-trefoil fold
  • ICE cut site
  • interleukin-I receptor
  • interleukin-I receptor accessory protein
  • comparative immunology
  • TROUT ONCORHYNCHUS-MYKISS
  • FIBROBLAST GROWTH-FACTORS
  • INTERLEUKIN-1 RECEPTOR
  • MOLECULAR-CLONING
  • RHEUMATOID-ARTHRITIS
  • CRYSTAL-STRUCTURE
  • EXPRESSION ANALYSIS
  • ACCESSORY PROTEIN
  • SALMO-SALAR
  • IN-VITRO

Cite this