title: Proreceptor dimerization is required for insulin receptor post-translational processing.
abstract: The insulin receptor is a transmembrane protein dimer composed of two alphabeta monomers held together by inter-alpha-chain disulfide bonds. In a previous report we described a monomeric insulin receptor obtained by replacing Cys-524, -682, -683, and -685 with serine. The membrane-bound monomeric insulin receptors could be cross-linked to dimers in the presence of insulin, indicating that although covalent interactions had been abolished, noncovalent dimerization could still occur in the membrane. To eliminate noncovalent dimerization, we replaced all or some of Cys-524, -682, -683, and -685 with arginine or aspartic acid with the expectation that the electrostatic repulsion at these contact sites would prevent noncovalent dimerization. The results indicate that mutant insulin receptors that are able to form covalent dimers are expressed at the wild type level; mutants that can form noncovalent dimers are expressed at half the level of the wild type receptor, whereas insulin receptor mutants that cannot dimerize are expressed at less than 10% of the wild type level. To elucidate the mechanism of the decrease in expression of the mutant insulin receptors, we examined their subcellular localization and biosynthesis. The results suggest that the extent of expression of these mutant receptors is related to their ability to form covalent or noncovalent dimers at the proreceptor stage.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: James Jianping
authors.initials: JJ
authors.lastname: Wu
authors.forename: Guido
authors.initials: G
authors.lastname: Guidotti
mesh_terms: D000818:Animals; D019556:COS Cells; D019281:Dimerization; D006801:Humans; D017510:Protein Folding; D011498:Protein Precursors / Q000032:analysis / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D011972:Receptor, Insulin / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry
chemical_list: D011498:Protein Precursors; D011972:Receptor, Insulin