Docking site

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 NHR contains also the conserved Calcineurin docking site, PxlxIT, required for the physical interaction of NEAT and Calcineurin. Dephosphorylation of at least 13 serines residues in the NHR induces a conformational change that exposes the nuclear localization sequences (NLS), allowing the nuclear translocation of NEAT. Rephosphorylation of these residues unmasks the nuclear export sequences that direct transport back to the cytoplasm. Engagement of receptors such as the antigen receptors in T and B cells is coupled to phospholipase C activation and subsequent production of inositol triphosphate. Increased levels of inositol triphosphate lead to the initial release of intracellular stores of calcium. This early increase of calcium induces opening of the plasma membrane calcium-released-activated-calcium (CRAC) channels,... 

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. 

Inhibitors that Interfere with Docking Sites... 

The RTK activity phosphorylates tyrosine residues within the intracellular domain of the receptor. These phosphorylated residues function as docking sites for proteins that will convey the signal to downstream signal transduction components. PKI can be developed that bind these phosphorylated docking sites in order to abrogate inappropriate downstream signalling. 

Induction of expression of various adhesion molecules on the surface of vascular endothelial cells. These act as docking sites for neutrophils, monocytes and lymphocytes, facilitating their accumulation at local sites of inflammation. 

The cytoplasmic domain primarily consists of the catalytic domain and various autophosphorylation sites that regulate catalytic function and serve as docking sites for SH2 do main-containing proteins. The protein kinase catalytic domains of RPTKs are highly conserved and similar in structure to those of the NRPTK (see above). 

Fig. 2. Presentation of the intracellular domain of the PDGF (platelet-derived growth factor) receptor. The two catalytically active kinase domains are highlighted. Docking sites for SH2 domains are symbolized with a pTyr sidechain. SH2 domains identified to bind to the corresponding phosphorylated tyrosines (numbered on the left) are schematically depicted and labeled on the right...

---