Binding specificity and intramolecular signal transmission of uncleaved insulin proreceptor in transformed lymphocytes from a patient with extreme insulin resistance.

Abstract

An alteration of an amino acid sequence in the processing site of the insulin proreceptor by a point mutation of the insulin receptor gene produced extreme insulin resistance. We characterized functional properties of the unprocessed insulin receptor in transformed lymphocytes from a patient. Insulin binding to intact cells and to a partially purified insulin receptor preparation was radically decreased to 20% and 18% of the control values, respectively. In competitive insulin binding to intact cells, [LeuA3]-, [LeuB24]-, [SerB24]-insulin, and mini-proinsulin ([ B(1-29)-Ala-Ala-Lys-A(1-21)]-insulin) had the same relative binding activity in both the patient's and the control cells, but proinsulin and IGF-I were markedly less able to displace 125I-insulin in the patient's cells. In contrast to the study in intact cells, proinsulin and IGF-I as well as other insulin analogues had the same relative binding activity to bind to the partially lectin-purified insulin receptor preparations from both the patient's and the control cells. As regards the signal transduction after receptor binding, insulin-stimulated autophosphorylation of the unprocessed insulin proreceptor occurred proportionally to the amount of decreased insulin binding. With 0.025% trypsin treatment, the abnormal binding characteristics and autophosphorylation were normalized through conversion to functionally normal receptors. In spite of the abnormal processing, self-association of receptors into oligomeric structures was observed in the proreceptor. These results suggest that the unprocessed insulin proreceptor in the plasma membranes has an altered conformation which affects its binding characteristics but not its intramolecular signal transmission.

• Authors: T Sasaoka, Y Shigeta, Y Takata, M Sugibayashi, A Hisatomi, M Kobayashi
• Journal: Diabetologia (Diabetologia) Vol. 32 Issue 6 Pg. 371-7 (Jun 1989) ISSN: 0012-186X [Print] Germany
• PMID: 2668084 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Protein Precursors
• insulin proreceptor
• Receptor, Insulin

Topics

• Adult
• Amino Acid Sequence
• Binding, Competitive
• Consanguinity
• Diabetes Mellitus, Type 1 (genetics, immunology, physiopathology)
• Female
• Humans
• Insulin (metabolism)
• Insulin Resistance
• Lymphocyte Activation
• Lymphocytes (immunology, metabolism)
• Molecular Sequence Data
• Mutation
• Phosphorylation
• Protein Precursors (genetics, metabolism, physiology)
• Receptor, Insulin (genetics, metabolism, physiology)
• Reference Values
• Signal Transduction