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.
Department of Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, California 91010.
P
P
De Meyts
J L
JL
Gu
R M
RM
Shymko
B E
BE
Kaplan
G I
GI
Bell
J
J
Whittaker
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