Identification of a ligand-binding region of the human insulin receptor encoded by the second exon of the gene.
Structure-function studies of the insulin molecule indicate that an insulin B chain domain comprising residues 22-26 is involved both in binding to the insulin receptor (INSR) and in insulin dimer formation, suggesting that this domain might also interact with a structure resembling the insulin dimer interface in the INSR. Expression of a mutant INSR cDNA with a deletion of the region corresponding to exon 2 of the INSR gene produces a protein devoid of insulin-binding activity, although the mutant protein is processed appropriately to alpha- and beta-subunits, suggesting that the insulin-binding domain is encoded at least in part by exon 2. Within this region of the INSR molecule, the sequence 83-103 fulfills the structural criteria for a dimer interface. Studies of mutant INSRs with substitutions for phenylalanine 88 or 89 show that the presence of phenylalanine at position 89 is essential for full binding affinity.
De Meyts
P
P
Department of Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, California 91010.
Gu
J L
JL
Shymko
R M
RM
Kaplan
B E
BE
Bell
G I
GI
Whittaker
J
J
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D005091:Exons; D005796:Genes / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D010649:Phenylalanine / Q000032:analysis; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection
D007328:Insulin; D008024:Ligands; D010649:Phenylalanine; D004247:DNA; D011972:Receptor, Insulin