Receptor tyrosine kinase domain structure

Mohammadi, M., Schlessinger, J., and Hubbard, S. R., Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism, Cell, 86, 577-578, 1996. 

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 Sema domain consisting of about 500 amino acids is characterized by highly conserved cysteine residues that form intramolecular disulfide bonds. Crystal structures have revealed that the Sema domain folds in the manner of the (3 propeller topology which is also found in integrins or the low-density lipoprotein (LDL) receptors. Sema domains are found in semaphorins, plexins and in the receptor tyrosine kinases Met and Ron. 

STRUCTURAL STUDIES OF RECEPTOR TYROSINE KINASES 4.5.1 Ligand-Binding Domains... 

FIGURE 24-10 Schematic structures of nonreceptor protein tyrosine phosphatases (NRPTPs) and receptor protein tyrosine phosphatases (RPTPs). NRPTPs contain a catalytic domain and various regulatory domains. RPTPs are composed of an extracellular domain, a transmembrane domain and an intracellular domain with one or two catalytic domains. Like receptor protein tyrosine kinases, the structural features of the extracellular domains divide the RPTPs into different families. (With permission from reference [12]). 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

Phosphohpases of type Cy are activated by receptor tyrosine kinases (see Chapter 8), and thus phosphohpase Cy is involved in growth factor controlled signal transduction pathways. The receptor tyrosine kinases (see Chapter 8) phosphorylate the enzyme at specific tyrosine residues and initiate activation of the enzyme. Characteristic for the structure of phospholipase Cy is the occurrence of SH2 and SH3 domains (see Chapter 8). These represent protein modules that serve to attach further partner proteins. 

Receptor tyrosine kinases are integral membrane proteins that have a hgand-binding domain on the extracellular side and a tyrosine kinase domain on the cytosohc side (see Fig. 8.1). The transmembrane portion is made up of just one structural element thus it is assumed that it crosses the membrane in an a-hehcal form. On the cytoplasmic side, in addition to the conserved tyrosine kinase domain, there are also further regulatory sequence portions at which autophosphorylation, and phosphorylation and dephosphorylation by other protein kinases and by protein phosphatases, can take place. 

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).

Cytoplasmically localized protein tyrosine phosphatases have a catalytic domain and other structural elements that specify the subcellular localization and association with effector molecules. These structural elements contain sequence signals for nuclear localization, for membrane association and for association with the cytoskeleton (see Fig. 8.16). The presence of SH2 domains suggests that these molecules might interact with signaling pathways involving growth hormones and receptor tyrosine kinases. 

Himanen, J.-P. et al. (1998). Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2. Nature 396, 486-491. 

Smalla, M. et al (1999). Solution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites. Protein Sci. 8, 1954-1961. 

The insulin receptor is the prototype of a t3rrosine kinase receptor with a constimtive, oligomeric structure (Chapter 1). The receptor has been cloned and characterized in detail, notably by Axel Ullrich, R. C. Kahn and colleagues, see Chapter 1.29 Binding of insulin stimulates the intrinsic receptor tyrosine kinase. A crystal structure of the tyrosine kinase domain of the insulin receptor was solved. This leads to phosphorylation of tyrosine residues and to the recruitment and subsequent phosphorylation of substrates. 

S. R Hubbard, L. Wei, L. Ellis and W A. Hendrickson. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature, 372, 746-754, 1994. 

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