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

26 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

Analysis of Fish IL-1ß and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design. / Koussounnadis, A. I.; Ritchie, David William; Kemp, G. J. L.; Secombes, Christopher John.

In: Current Pharmaceutical Design, Vol. 10, No. 31, 12.2004, p. 3857-3871.

Research output: Contribution to journalArticle

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T1 - Analysis of Fish IL-1ß and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design

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AU - Ritchie, David William

AU - Kemp, G. J. L.

AU - Secombes, Christopher John

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AB - 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.

KW - Interleukin-1

KW - beta-trefoil fold

KW - ICE cut site

KW - interleukin-I receptor

KW - interleukin-I receptor accessory protein

KW - comparative immunology

KW - TROUT ONCORHYNCHUS-MYKISS

KW - FIBROBLAST GROWTH-FACTORS

KW - INTERLEUKIN-1 RECEPTOR

KW - MOLECULAR-CLONING

KW - RHEUMATOID-ARTHRITIS

KW - CRYSTAL-STRUCTURE

KW - EXPRESSION ANALYSIS

KW - ACCESSORY PROTEIN

KW - SALMO-SALAR

KW - IN-VITRO

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DO - 10.2174/1381612043382585

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VL - 10

SP - 3857

EP - 3871

JO - Current Pharmaceutical Design

JF - Current Pharmaceutical Design

SN - 1381-6128

IS - 31

ER -