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Insulin Receptor Tyrosine Kinase

Michael P. Czech, Barbara Van Renterghem, Mark W. Sleeman

10.1002/cphy.cp070211

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Insulin Receptor Structure
1.1 Insulin Binding
1.2 Receptor Endocytosis Motifs
1.3 Tyrosine Kinase Characteristics
2 Insulin Receptor Substrates
2.1 Pleckstrin Homology Domains
2.2 Phosphotyrosine‐Binding Domains
2.3 Src Homology 2 Domains
Figure 1. Figure 1.

Structure of the insulin receptor kinase. The insulin receptor is a heterotetrameric protein composed of two extracellular α subunits linked by disulfide bonds to each other (class I) or to the β subunits (class II). The β subunits contain multiple phosphorylation sites in three regions, including the juxtamembrane region (Tyr‐960), a regulatory region (Tyr‐1146, Tyr‐1150, and Tyr‐1151), and the C terminus (Tyr‐1316, and Tyr‐1322). The regulatory domain tyrosine residues play a major role in the activation of the receptor kinase, while those outside this domain in the juxtamembrane region mediate the association and phosphorylation of insulin receptor substrates. Residue Tyr‐960, located in an NPXY motif, interacts with the phosphotyrosine‐binding domains of Shc and the insulin receptor substrate proteins.
Figure 2. Figure 2.

Ribbon diagram of the activated tris‐phosphorylated insulin receptor kinase (IRK‐3P). Secondary structural components, α helices (red) and β sheets (blue), are labeled. The nucleotide‐binding loop is in yellow, the catalytic loop in orange, the activation loop in green, AMP‐purine nucleoside phosphorylase in black, and the peptide substrate in pink. The termini are denoted by N (amino terminus) and C (carboxyl terminus).

[From Hubbard et al. 52 with permission.]
Figure 3. Figure 3.

Space‐filling model of the comparison of the activation loop conformations in insulin receptor kinase (IRK) and the activated tris‐phosphorylated insulin receptor kinase (IRK‐3P). The activation loop is shown in green, the catalytic loop in orange, the peptide substrate in pink, and the rest of the protein as a semitransparent molecular surface. The AMP‐purine nucleoside phosphorylase is partially masked by the amino‐terminal lobe of IRK‐3P. Carbon atoms are shown in white, nitrogen in blue, oxygen in red, and phosphorus in yellow.

[From Hubbard 51 with permission.]


Figure 1.

Structure of the insulin receptor kinase. The insulin receptor is a heterotetrameric protein composed of two extracellular α subunits linked by disulfide bonds to each other (class I) or to the β subunits (class II). The β subunits contain multiple phosphorylation sites in three regions, including the juxtamembrane region (Tyr‐960), a regulatory region (Tyr‐1146, Tyr‐1150, and Tyr‐1151), and the C terminus (Tyr‐1316, and Tyr‐1322). The regulatory domain tyrosine residues play a major role in the activation of the receptor kinase, while those outside this domain in the juxtamembrane region mediate the association and phosphorylation of insulin receptor substrates. Residue Tyr‐960, located in an NPXY motif, interacts with the phosphotyrosine‐binding domains of Shc and the insulin receptor substrate proteins.



Figure 2.

Ribbon diagram of the activated tris‐phosphorylated insulin receptor kinase (IRK‐3P). Secondary structural components, α helices (red) and β sheets (blue), are labeled. The nucleotide‐binding loop is in yellow, the catalytic loop in orange, the activation loop in green, AMP‐purine nucleoside phosphorylase in black, and the peptide substrate in pink. The termini are denoted by N (amino terminus) and C (carboxyl terminus).

[From Hubbard et al. 52 with permission.]


Figure 3.

Space‐filling model of the comparison of the activation loop conformations in insulin receptor kinase (IRK) and the activated tris‐phosphorylated insulin receptor kinase (IRK‐3P). The activation loop is shown in green, the catalytic loop in orange, the peptide substrate in pink, and the rest of the protein as a semitransparent molecular surface. The AMP‐purine nucleoside phosphorylase is partially masked by the amino‐terminal lobe of IRK‐3P. Carbon atoms are shown in white, nitrogen in blue, oxygen in red, and phosphorus in yellow.

[From Hubbard 51 with permission.]
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Article Title: Insulin Receptor Tyrosine Kinase
 

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Michael P. Czech, Barbara Van Renterghem, Mark W. Sleeman. Insulin Receptor Tyrosine Kinase. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 399-411. First published in print 2001. doi: 10.1002/cphy.cp070211