Role of proline 193 in the insulin receptor post-translational processing

D. Maggi, F. Barbetti, R. Cordera

Research output: Contribution to journalArticlepeer-review

Abstract

Aims/hypothesis. A point mutation, P193L, in the insulin receptor α subunit, has been previously identified in a patient affected by an extreme form of insulin resistance due to reduced insulin binding. In our study we investigated the cellular mechanisms by which P193L substitution causes a reduction of insulin receptor numbers on the cell surface. Methods. Mutated insulin receptors have been generated and expressed in COS1 cells. Transcription as well as translation of P193L insulin receptor have been measured and compared with wild type insulin receptor. Results. P193L insulin receptor is normally transcribed and progresses to the step of insulin proreceptor, which does not proceed to dimerization, resulting in the accumulation of the 210 kDa form. These findings suggest that the P193L insulin proreceptor is retained in the endoplasmic reticulum, where several molecular chaperones drive the folding of protein precursors. Therefore the interaction between mutated insulin receptor precursor and two endoplasmic reticulum resident chaperones (GRP78 and calnexin) were investigated. P193L insulin proreceptor co-immunoprecipitates with greater amounts of GRP78 and its interaction with calnexin is greatly delayed compared with wild type insulin receptor precursor. Co-transfection of wild type and mutated insulin receptors causes a considerable reduction of cell surface wild type insulin receptors. Conclusion/interpretation. P193 is critical for insulin proreceptor folding. The monomeric form of P193L insulin proreceptor is retained in the endoplasmic reticulum by a calnexin and GRP78 mediated mechanism that reduces mature insulin receptor expression on the cell surface.

Original languageEnglish
Pages (from-to)435-442
Number of pages8
JournalDiabetologia
Volume42
Issue number4
DOIs
Publication statusPublished - 1999

Keywords

  • Calnexin
  • GRP78
  • Insulin receptor processing
  • Insulin resistance
  • P193L mutation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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