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 language | English |
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Pages (from-to) | 3857-3871 |
Number of pages | 14 |
Journal | Current Pharmaceutical Design |
Volume | 10 |
Issue number | 31 |
DOIs | |
Publication status | Published - 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