Analysis of fish IL-1beta and derived peptide sequences indicates conserved structures with species-specific IL-1 receptor binding: implications for pharmacological design.
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-evolution. 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.
Koussounadis
Antonis I
AI
Department of Computing Science, King's College, University of Aberdeen, Aberdeen AB24 3UE, UK. akoussou@csd.abdn.ac.uk
Ritchie
David W
DW
Kemp
Graham J L
GJ
Secombes
Chris J
CJ
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017322:Clinical Trials, Phase II as Topic; D017124:Conserved Sequence / Q000502:physiology*; D015195:Drug Design; D005399:Fishes / Q000145:classification / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry*; D008969:Molecular Sequence Data; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D020539:Sequence Analysis, Protein; D013045:Species Specificity
D007375:Interleukin-1; D017472:Receptors, Interleukin-1