Insulin receptor protein tyrosine kinase domain structure

Fig. 8.7. Structure of the catalytic domain of the insulin receptor. The crystal structure of the tyrosine kinase domain of the insulin receptor (Hubbard et al., 1994) has a two-lobe structure that is very similar to the structure of the Ser/Thr-specific protein kinases. Structural elements of catalytic and regulatory importance are shown. The P loop mediates binding of the phosphate residue of ATP the catalytic loop contains a catalytically essential Asp and Asn residue, found in equivalent positions as conserved residues in many Ser/Thr-specific and Tyr-specific protein kinases. Access to the active center is blocked by a regulatory loop containing three Tyr residues (Tyrll58, Tyrll62 and Tyrll63). Tyrll62 undergoes autophosphorylation in the course of activation of the insulin receptor. MOLSKRIPT representation according to Kraulis, (1991).

The core of all eukaryotic Ser/Thr- and Tyr-specific protein kinases adopt a common fold illustrated in Fig. 7.3 for the tyrosine kinase domain of the insulin receptor. The structure comprises two lobes that are conneded by a hinge region. The N-terminal lobe contains five / -structures and one a-helix, named C-helix. In contrast, the larger C-terminal lobe is mostly a-helical. It comprises a four-helix bundle, additional a-he-lices, and two short yS-strands. ATP and 1 or 2 metal ions are bound at the interface of the two lobes, while the binding site for the peptide substrate is located mostly in the C-terminal lobe. The following structural elements have been found to be critical for catalysis and for protein kinase control ... 

A case in point is the structure determination of the insulin receptor substrate-1 (IRS-1). Insulin binds to a membrane-bound receptor that is a ligand-activated protein tyrosine kinase. Upon insulin binding there is an autophosphorylation of several tyrosine residues on the cytosolic side of the receptor. This enhances the tyrosine kinase activity of the insulin receptor towards other substrates and is required for signal transduction. A cascade of events is initiated, the first of which is the phosphorylation of IRS-1. This occurs when IRS-1 binds to the insulin receptor via a specific domain of the protein that is termed the phosphotyrosine binding (PTB) domain. 

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. 

Figure 14.19 Activation of the insulin receptor by phosphorylation. The activation loop is shown in red in this model of the protein kinase domain of the fi subunit of The Insulin receptor. The unphosphorylated structure on the left is not catalytically active. Notice that, when three tyrosine residues in the activation loop are phosphorylated, the activation loop swings across the structure and the kinase structure adopts a more compact conformation. This conformation is catalytically active. [Drawn from lIRK.pdb and IR3.pdb.]...

Figure 14.21 The modular structure of Insulin receptor substrates IRS-1 and IRS-2 This schematic view represents the amino acid sequence common to IRS-1 and lRS-2. Each protein contains a pleckstrin homology domain (which binds phosphoinositide lipids), a phospbotyrosine-binding domain, and four sequences that approximate Tyr-X-X-Met (YXXM). The latter are phosphorylated by the insulin receptor tyrosine kinase.

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