Residuals platelet derived growth factor

Ohvera, A., Edsall, L., Poulton, S., Kazlauskas, A. and Spiegel, S., 1999, Platelet-derived growth factor-induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLCy, FASEB J. 13 1593-1600. 

The insulin receptor is the prototype for a number of receptor enzymes with a similar structure and receptor Tyr kinase activity. The receptors for epidermal growth factor and platelet-derived growth factor, for example, have structural and sequence similarities to the insulin receptor, and both have a protein Tyr kinase activity that phosphorylates IRS-1. Many of these receptors dimerize after binding ligand the insulin receptor is already a dimer before insulin binds. The binding of adaptor proteins such as Grb2 to (P) Tyr residues is a common mechanism for promoting protein-protein interactions, a subject to which we return in Section 12.5. 

A group of receptors exists that responds to so-called growth factors such as insulin, epidermal growth factor, platelet-derived growth factor, etc. These receptors have an extracellular domain that binds the growth factor and an intracellular domain that possesses latent kinase activity. The interaction of insulin, for example, results in autophosphorylation of the intracellular domain and subsequent internalization of the insulin-receptor complex. The internalized complex now possesses the properties of a tyrosine kinase and can phosphorylate cell substrates that produce the appropriate intracellular effect. However, these kinases differ from the usual protein kinases in that they phosphorylate proteins exclusively on tyrosine hydroxyl residues. The ensemble of proteins phosphorylated by the insulin receptor has not yet been identified, but there is supportive evidence that tyrosine kinase activity is required for the major actions of insulin. For example, it is possible that a membrane-linked glucose transport system becomes activated following insulin-stimulated phosphorylation. 

The structure of the N-SHP-2 SH2 domain in complex with peptides based on the platelet-derived growth factor receptor (PDGFR) and the adapter protein IRSl revealed that the interaction between the protein and the peptide is extended to the residue 5 positions C-terminal to the pTyr (Lee et al., 1994). In these structures, the +3 position binding pocket is opened in order to create such an extended interface. The interactions between the peptide and the protein are primarily hydro-phobic. For example, a Phe at the +5 position of the IRSl peptide binds between the EF and BG loops and interacts with the He at the +3 position (Lee et al., 1994). Other than this extended interface, the interactions in this structure are reminiscent of those observed in the Src SH2 domain structure the peptide binds in an extended conformation perpendicular to the central (3-sheet. 

CYP163B3 (P450sky) from Streptomyces sp. Acta 2897 is involved in the biosynthesis of the cyclic depsipeptides skyllamycin A and B, with antibacterial, immunosuppressive, cytostatic, and antiparasitic properties [233], Skyllamycin A has been isolated from different Streptomyces strains and is a potent inhibitor of the platelet-derived growth factor (PDGF) signaling pathway that is involved in important processes such as cellular proliferation and migration [234, 235]. The structure of skyllamycin has an unusual a-hydroxylated glycine residue, an N-terminal cinnamoyl side chain, and three P-hydroxylated amino acids ((25, 55)-p-hydroxyphenylalanine,... 

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