A region of the insulin receptor important for ligand binding (residues 450-601) is recognized by patients' autoimmune antibodies and inhibitory monoclonal antibodies.
Chimeric receptors containing different portions of the homologous human insulin receptor, insulin-like growth factor I receptor, and insulin receptor-related receptor were utilized to identify the epitopes recognized by various anti-insulin receptor antibodies. The antibodies studied included 12 monoclonal antibodies to the extracellular domain of the human insulin receptor as well as 15 patients' sera with autoimmune anti-insulin receptor antibodies. All of the patients' sera and all 8 monoclonal antibodies that inhibit insulin binding were found to recognize an epitope contained within residues 450-601 of the alpha subunit of the receptor. In contrast, 2 monoclonal antibodies that do not inhibit insulin binding were found to recognize the cysteine-rich region of the alpha subunit. Chimeric insulin receptors that had residues 450-601 replaced with the homologous residues of the insulin-like growth factor I receptor exhibited a decreased ability to bind insulin. In contrast, insulin-like growth factor I receptors that have had the comparable region replaced with that of the insulin receptor showed no decrease in their ability to bind ligand. These results indicate that residues 450-601 of the insulin receptor are important for insulin binding and include the major site for recognition by inhibitory monoclonal antibodies and patients' autoimmune anti-receptor antibodies.
Zhang
B
B
Department of Pharmacology, Stanford University School of Medicine, CA 94305.
Roth
R A
RA
D000911:Antibodies, Monoclonal / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D015153:Blotting, Western; D003001:Cloning, Molecular; D000939:Epitopes; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D011972:Receptor, Insulin / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007328:Insulin; D008024:Ligands; D009841:Oligonucleotides; D011993:Recombinant Fusion Proteins; D011972:Receptor, Insulin