Receptor structure, insulin

M. P. Czech (1985). The nature and regulation of the insulin receptor structure and function. Annu. Rev. Physiol. 47 357-391. 

E. van Obberghen, S. Gammeltoft (1986). Insulin receptors structure and function. Experientia 42 727-734. 

Massague, J., Pilch, P.F. and Czech, M.P. (1980) Electrophoretic resolution of three major insulin receptor structures with unique subunit stoichiometries. Proc. Natl. Acad.. Sci. USA 77 7137-7141. 

Constans, T., Chevalier, B., Derouet, M. Simon, J. (1991). Insulin sensitivity and liver insulin receptor structure in ducks from two genera. Am. ]. Physiol., 261, R882-90. 

Fig. 1. Insulin receptor. Structure of the precursor polypeptide of the insuiin receptor. A sequence of basic amino acids (in this case Argg, LySg42 Argg43) at the junction of the transmembrane sequence and the cytoplasmic domain is a common feature of transmembrane proteins. It is thought that they interact with polar groups of phospholipids on the membrane surface.

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. 

The insulin-like growth factor I receptor is closely related to the insulin receptor. The RTK activity of the IGF-I receptor is regulated by intermolecular autophosphorylation at three sites within the activation loop. The crystal structure of the trisphosphorylated form of IGF-I RTK domain with an ATP analog and a specific peptide substrate showed that autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Furthermore, the structure revealed how... 

Gammeltoft, S., Insulin receptors binding kinetics and structure-function relationship of insulin, Physiol. Rev., 64, 1321-1378, 1984. 

Hubbard, S. R., Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog, EMBO J., 16, 5572-5581, 1997. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

Fig. 12. 3D Structure of a pTyr-containing oligopeptide bound to the IRS-1 (insulin receptor substrate) PTB domain (lIRS.pdb). The Asn-Pro-Ala-pTyr tetrapeptide sequence adopts a regular pi turn conformation [181]...

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. 

A challenge posed to researchers was therefore to account for diverse physiological effects emanating from the same receptor/hormone interaction. Structurally, the insulin receptor (IR) is a tetrameric protein, composed of two smaller extracellular a units and two larger transmembrane [3 units (see Figure 4.20a). 

Hawkes C, Kar S. 2004. The insulin-like growth factor-II/ mannose-6-phosphate receptor structure, distribution and function in the central nervous system. Brain Res Rev 44 117-140. 

Figure 7.1. Comparison of the structure of the lGF-1, IGF-2 and the insulin receptors. Refer to text for...

Recent studies also point to the existence of a fourth receptor species. This appears to be a hybrid structure, composed of an insulin receptor a-/l dimer crosslinked to an IGF-1 receptor oc-fi dimer. Although this receptor type displays a marked reduction in its affinity for insulin. 

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