STRUCTURE-FUNCTION ANALYSIS OF HUMAN IL-1-ALPHA - IDENTIFICATION OF RESIDUES REQUIRED FOR BINDING TO THE HUMAN TYPE-I IL-1 RECEPTOR

Using oligonucleotide-directed mutagenesis, the binding site on human interleukin-1alpha (IL-1alpha) for the human type I IL-1 receptor (IL-1R) has been analyzed. Substitution of seven amino acids (Arg12, Ile14, Asp60, Asp61, Ile64, Lys96 and Trp109) resulted in a significant loss of binding to the receptor. Based on crystallographic information, the side chains of these residues are clustered in one region of IL-1alpha and exposed on the surface of the protein. Five of the residues in the IL-1alpha binding site align with the binding residues previously determined in human IL-1beta, demonstrating that the type I IL-IR recognizes homologous regions in both ligands. Unexpectedly, only three of the aligned residues are identical between IL-1alpha and IL-1beta. These observations suggest that the composition of contact residues in the binding site is unique for each ligand - receptor complex in the IL-1 system.