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GTP-binding protein-activator sequences in the insulin receptor
T Okamoto1, T Okamoto, Y Murayama
1Department of Medicine, Harvard Medical School, Charlestown, MA 02129.
FEBS Letters
|November 8, 1993
Summary
Researchers identified specific domains within the human insulin receptor (insR) that activate G proteins. Autophosphorylation of these domains modifies their G protein activation capabilities, offering new insights into insR signaling pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Endocrinology
Background:
- Insulin receptor (insR) functions are partly mediated by pertussis toxin-sensitive Gi/G(o) proteins.
- The precise locations and regulation of G-protein-activating domains within insR remain largely uncharacterized.
Purpose of the Study:
- To identify and characterize G-protein-activator domains within the cytoplasmic region of the human insulin receptor.
- To investigate the role of autophosphorylation in modulating the activity of these domains.
Main Methods:
- Bioinformatic analysis of the human insR sequence to identify candidate G-protein-activator domains (ISRP1, ISRP2, ISRP3).
- In vitro assays to assess the G-protein activating function of identified peptides.
- Analysis of the effect of tyrosine autophosphorylation on the G-protein activating capabilities of ISRP2 and ISRP3.
Main Results:
- Three candidate G-protein-activator domains (ISRP1, ISRP2, ISRP3) were identified in the insR cytoplasmic region.
- ISRP3 demonstrated Gi/G(o)-activating function, while ISRP1 activated Gs, and ISRP2 showed no basal G protein activation.
- Tyrosine autophosphorylation enhanced ISRP2's Gi-activating function and broadened ISRP3's activation to multiple G proteins.
Conclusions:
- This study provides the first identification of specific G-protein-activator domains within the insulin receptor.
- Autophosphorylation significantly modifies the G protein coupling specificity and potency of these domains, revealing a novel regulatory mechanism for insR signaling.