Insulin initiates its biological response by binding to the extracellular domain of the insulin receptor. The N-terminal half of the α-subunit contains several repeats of a loosely conserved motif consisting of a central glycine plus several hydrophobic amino acid residues upstream from the glycine, Hyφ-Xaa-Xaa-Hyφ-Xaa-Hyφ-Hyφ-Xaa-Gly (where Hyφ represents a hydrophobic amino acid residue). This structural motif has been proposed to be important in determining the three-dimensional structure of the insulin binding domain. We have identified two naturally occurring mutant alleles of the insulin receptor gene in an insulin-resistant patient, substitution of Ala for Val28 and Arg for Gly366. The mutations alter conserved amino acid residues in two distinct repeats of the structural motif described above. When mutant cDNAs were expressed in NIH-3T3 cells, both mutations severely impaired proteolytic processing of the proreceptor to mature α- and β-subunits. Transport of mutant receptors to the plasma membrane was also impaired. However, the minority (28 and Arg366 mutations prevent normal folding of the insulin receptor α-subunit, thereby inhibiting post-translational processing and intracellular transport of the mutant receptors.
|Number of pages||6|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - Mar 11 1994|
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