title: A novel human insulin receptor gene mutation uniquely inhibits insulin binding without impairing posttranslational processing.
abstract: The precise nature of the insulin-binding site of the insulin receptor (IR) has not been determined, although the importance of several regions of the alpha-subunit in insulin binding has been demonstrated. A naturally occurring mutation in a patient with severe insulin resistance that changes the Ser323 codon in the alpha-subunit of the IR to a leucine codon is associated with markedly impaired insulin binding to cells from the patient and to transfected cells expressing the mutant receptor. However, unlike other IR alpha-subunit mutations associated with decreased insulin binding, this mutation does not lead to a defect in posttranslational processing or cell-surface expression of IRs. Thus, the defect in insulin binding associated with the Leu323 mutant IR is a direct result of an alteration in the insulin-binding site. No natural IR mutation described thus far is associated with both decreased insulin binding and normal cell-surface expression of the mutant receptor. This study demonstrates the critical role that Ser323 of the IR alpha-subunit plays in insulin binding, either by forming part of the binding site or by stabilizing its conformation.
authors.affiliation: Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: P
authors.initials: P
authors.lastname: Roach
authors.forename: Y
authors.initials: Y
authors.lastname: Zick
authors.forename: P
authors.initials: P
authors.lastname: Formisano
authors.forename: D
authors.initials: D
authors.lastname: Accili
authors.forename: S I
authors.initials: SI
authors.lastname: Taylor
authors.forename: P
authors.initials: P
authors.lastname: Gorden
mesh_terms: D016475:3T3 Cells; D000015:Abnormalities, Multiple / Q000097:blood / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D003062:Codon; D004247:DNA / Q000097:blood / Q000302:isolation & purification; D005091:Exons; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D009679:Nuclear Family; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D011972:Receptor, Insulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012694:Serine; D013577:Syndrome; D014162:Transfection
chemical_list: D003062:Codon; D007328:Insulin; D012694:Serine; D004247:DNA; D011972:Receptor, Insulin