Substitution of arginine for histidine at position 209 in the alpha-subunit of the human insulin receptor. A mutation that impairs receptor dimerization and transport of receptors to the cell surface.
Receptors for insulin and epidermal growth factor contain cysteine-rich domains in the extracellular portion of the molecule. His209 (insulin receptor numbering system) is 1 of 2 amino acid residues that are identically conserved in the cysteine-rich domains of insulin receptors, epidermal growth factor receptors, and other homologous receptors. Previously, we have identified a patient with leprechaunism who is homozygous for a mutation substituting Arg for His209 in the insulin receptor gene (Kadowaki, T., Kadowaki, H., Rechler, M. M., Serrano-Rios, M., Roth, J., Gorden, P., and Taylor, S. I. (1990) J. Clin. Invest. 86, 254-264). In this investigation, the Arg209 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells. The mutation impairs several steps in the post-translational processing of the insulin receptor:dimerization of 190-kDa proreceptors into a disulfide linked species, proteolytic cleavage of the proreceptor into alpha- and beta-subunits, and terminal processing of the high mannose form of N-linked oligosaccharide into complex carbohydrate. In addition, the defects in post-translational processing within the endoplasmic reticulum and Golgi apparatus are associated with a marked inhibition in transport of receptors to the plasma membrane. Nevertheless, a small number (approximately 10%) of the receptors are transported to the cell surface. These receptors on the cell surface bind insulin with normal affinity and have normal tyrosine kinase activity.
Kadowaki
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Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Kadowaki
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H
Accili
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D
Yazaki
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Y
Taylor
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SI
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000502:physiology; D001483:Base Sequence; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D006639:Histidine / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D007328:Insulin; D046911:Macromolecular Substances; D006639:Histidine; D001120:Arginine; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin