A novel human insulin receptor gene mutation uniquely inhibits insulin binding without impairing posttranslational processing

Paris Roach, Yehiel Zick, Pietro Formisano, Domenico Accili, Simeon I. Taylor, Phillip Gorden

Research output: Contribution to journalArticle

42 Scopus citations


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 α-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 α-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 α-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 α-subunit plays in insulin binding, either by forming part of the binding site or by stabilizing its conformation.

Original languageEnglish (US)
Pages (from-to)1096-1102
Number of pages7
Issue number9
StatePublished - Jan 1 1994


ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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