Insulin receptor functional domains

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

An important question arises about the effects of phospholipid composition and the function of membrane-bound enzymes. The phospholipid composition and cholesterol content in cell membranes of cultured cells can be modified, either by supplementing the medium with specific lipids or by incubation with different types of liposomes. Direct effects of phospholipid structure have been observed on the activity of the Ca2+-ATPase (due to changes in the phosphorylation and nucleotide binding domains) [37]. Evidence of a relationship between lipid structure and membrane functions also comes from studies with the insulin receptor [38]. Lipid alteration had no influence on insulin binding, but modified the kinetics of receptor autophosphorylation. 

In this context interest is focused on PKC, which plays a key role in mediating signals generated by hormones, growth factors and neurotransmitters (Nishizuka, 1988). Several isoforms of PKC have been described which show distinct sensitivity to Ca2+ and phospholipid-degradation products (Nishizuka, 1988). Their specific function, however, is not defined. It has been demonstrated previously that phorbol esters are potent activators of PKC and induce inhibition of the catalytic domain of the insulin receptor probably via serine phosphorylation of the insulin receptor )8-subunit (Muller et al., 1991). 

Receptors for different ligands have been characterized and show multiple functional domains (see low-density lipoproteins. Chapter 20 insulin. Chapter 22). 

Fig. 7.3 Structure of the tyrosine kinase domain of the Insulin receptor with bound ATP and peptide substrate (after Hubbard and Till, 2000). The a-helices are shown in red, the/ -strands in blue. The functional important structural elements are indicated. The P-loop is shown in yellow, the activation loop in green and the catalytic loop in orange. The amino and carboxy termini are denoted by N and C.

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