A point mutation uncouples human interleukin-1 beta biological activity and receptor binding.
Interleukin-1 proteins elicit a number of biological activities, but the molecular events following formation of a cell surface receptor-ligand complex have not been well defined. Conversion of Arg127 to Gly127 in the mature human interleukin-1 beta protein reduces bioactivity by 100-fold while the receptor binding affinity decreases by only 25%. The results suggest that the mutant IL-1 beta protein is defective in activating signal transduction events and indicate that binding of interleukin-1 beta protein to receptor is necessary but insufficient for biological activity. The finding that the features of the IL-1 beta protein responsible for receptor binding and biological activity are at least in part distinct may be clinically relevant to the design of interleukin-1 antagonists.
Gehrke
L
L
Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge 02139.
Jobling
S A
SA
Paik
L S
LS
McDonald
B
B
Rosenwasser
L J
LJ
Auron
P E
PE
D000595:Amino Acid Sequence; D001120:Arginine; D004261:DNA Replication / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005998:Glycine; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids; D014176:Protein Biosynthesis; D011487:Protein Conformation; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology
D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D001120:Arginine; D005998:Glycine