Structure and function of the insulin receptor-a personal perspective

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Insulin resistance and acanthosis nigricans are associated with defects in insulin receptor function.
• The precise molecular mechanisms underlying insulin receptor signaling remain under investigation.

Purpose of the Study:

• To elucidate the structure and enzymatic activity of the human insulin receptor.
• To investigate the role of insulin receptor tyrosine kinase activity in insulin action.

Main Methods:

• Immunoprecipitation using patient-derived autoantibodies against the insulin receptor.
• Biochemical assays involving purified insulin receptor and [γ-³²P]ATP.
• Genetic analysis and functional studies of a patient with a novel insulin receptor mutation.

Main Results:

• The insulin receptor consists of α (135 kDa) and β (95 kDa) subunits.
• Insulin stimulates rapid tyrosine phosphorylation of the β subunit, indicating the receptor is a tyrosine kinase.
• A mutation (Glycine-996 to Valine) in the ATP binding site of the insulin receptor gene impairs tyrosine kinase activity and insulin signaling.

Conclusions:

• The insulin receptor possesses intrinsic tyrosine-specific protein kinase activity.
• Tyrosine kinase activity of the insulin receptor is essential for mediating insulin action in vivo.
• Mutations affecting the kinase domain can lead to severe insulin resistance syndromes.