Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor. A mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding

Mutations in the insulin receptor gene can compromise the ability of the receptor to mediate insulin action. Previously, in investigations of a patient with a genetic form of insulin resistance, we have identified a mutant allele encoding an insulin receptor in which lysine is substituted for asparagine at position 15 of the alpha-subunit. In the present study, we have characterized the Lys15-mutant receptor expressed by transfection of mutant cDNA into NIH-3T3 cells. The Lys15-mutation causes at least two defects in insulin receptor function. First, the mutation retards the post-translational processing of the receptor and impairs transport of the receptor to the plasma membrane, thereby reducing the number of receptors on the cell surface. Second, the mutation causes a 5-fold reduction in the affinity of the receptor to bind insulin. These two defects combine to render the target cell resistant to normal physiological concentrations of insulin. It seems likely that both functional defects associated with the Lys15-mutation can be explained by assuming that the mutation distorts the three-dimensional structure of the receptor. Presumably, the abnormal conformation interferes with the transport of the receptor through the endoplasmic reticulum and Golgi, and also inhibits the binding of insulin to its binding site on the receptor.