Ligand-binding domains receptor tyrosine kinases

The IGF-I receptor is an a2 2 heterotetramer that is structurally similar to the insulin receptor but is coded for by a different, single-copy gene located within bands q25-26 of chromosome 15. Like the insulin receptor, with which it shares 50-60% sequence homology, the IGF-I receptor has a cysteine-rich domain in the a subunit for ligand binding and a tyrosine kinase domain in the... 

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

FIGURE 4.2 Receptor tyrosine kinase dimerization. Binding of monomeric or dimeric ligands to RTK monomers leads to formation and stabilization of activated RTK dimers. Cytoplasmic domains of RTK are trans-phosphorylated by active FTK. 

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

Figure 10.7 The EGF receptor. The N-terminal, extracellular region of the receptor contains 622 amino acids. It displays two cysteine-rich regions, between which the ligand-binding domain is located. A 23 amino acid hydrophobic domain spans the plasma membrane. The receptor cytoplasmic region contains some 542 amino acids. It displays a tyrosine kinase domain, which includes several tyrosine autophosphorylation sites, and an actin-binding domain that may facilitate interaction with the cell cytoskeleton...

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... 

Figure 4.20 Tyrosine kinase-linked receptors (a) those with inherentTK activity insulin receptor. The intracellular tail and cytoplasmic proteins become phosphoryLated following hormone engagement with the ligand-binding domain...

As in the case of other receptor tyrosine kinases like erbB 1 and erbB2, efforts have been directed to identify and develop hiunanized antibodies that block the physical interaction between IGF-IR and its cognate ligands. Although obtained by applying different approaches, these antibodies have been shown in a variety of preclinical systems to specifically bind to the extracellular domain of IGF-IR, preventing downstream signahng. 

Some transmembrane receptors possess intrinsic tyrosine kinase activity. These receptors are known as receptor tyrosine kinases. Ligand binding to an extracellular domain of the receptor is coupled to the stimulation of tyrosine kinase activity localized on a cytoplasmic receptor domain. The ligand binding domain and the tyrosine kinase domain are part of one and the same protein. 

Receptor tyrosine kinases possess binding sites at the surface of the cell membrane that are specific for extracellular ligands. Ligand binding to the receptor activates a tyrosine-specific protein kinase activity of the receptor, located on the cytoplasmic domain. Consequently, tyrosine phosphorylation is initiated, at the receptor itself and also on substrate proteins these in turn trigger the biological response of the cell by... 

Fig. 8.3. Ligand-induced autophosphorylation and substrate phosphorylation of receptor tyrosine kinases. The tyrosine kinase domain of the receptor tyrosine kinase is activated by ligand binding. Consequently, autophosphorylation and/or phosphorylation of substrate proteins takes place. The substrate proteins possess specific phosphotyrosine binding domains (SH2 in the figure or FTP domains, see 8.2), which bind to phosphate residues formed in the process of autophosphorylation.

The bacterial chemoreceptor (Figs. 11-8 and 19-5) has a very small ligand-binding domain and a larger internal domain that activates a histidine kinase. Many growth-factor receptors, including the insulin receptor (Figs. 11-11,11-12), have internal domains with protein tyrosine kinase activity. 

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