Phosphotyrosine binding domain

Benes CH, Wu N, Elia AE, Dharia T, Cantley LC, Soltoff SP. The C2 domain of protein kinase C-delta is a phosphotyrosine binding domain. Cell 2005 121 (2) 271-280. 

PACAP pituitary adenylyl cyclase-activating peptide PTB phosphotyrosine binding domain... 

PTB Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain E(M) 0(0) 11(11) 1AQC... 

Yankee, T. M., L. M. Keshvara, S. Sawasdikosol, M. L. Harrison, and R. L. Geahlen. Inhibition of signaling through the B cell antigen receptor by the protooncogene product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl phosphotyrosine-binding domain. J Immunol. 163 5827-35.1999. 

Fig. 6 Proteins with GPR motifs. (RBD Ras binding domain, PTB phosphotyrosine binding domain, RGS regulator of G-protein signaling domain, PDZ PSD95/DLG/ZO-1 domain, cc coiled-coil domain). This figure is adapted from the thesis of Dr. Yuri Peterson...

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.

Fig. 8.6. Functions of autophosphorylation of receptor tyrosine kinases. Autophosphorylation of receptor tyrosine kinases takes place in trans, i.e., between neighboring protomers of the receptor. The catalytic domain of the receptor is shown as a shaded segment. As a consequence of autophosphorylation, the intrinsic tyrosine kinase activity of the receptor is stimulated. Effector proteins can also bind to the activated receptor. Binding takes place with specific phosphotyrosine binding domains (SH2 or PTB domains) at phosphotyrosine residues of the activated receptor. A critical factor for further signal transduction is the membrane association of the effector proteins that enter into binding with the activated receptor. Details of the effector proteins can be found as follows phospholipase Cy 5.6.2 Src kinase 8.3.2 pl20 GAP 9.4 Grb2, She, IRS 8.5 PI3-kinase 6.6.1 Syp tyrosine phosphatase 8.4.

The phosphotyrosine residues of the activated receptors are attachment points for effector proteins that possess a phosphotyrosine binding domain, such as the SH2... 

Songyang and Cantely, 1995). Furthermore, another phosphotyrosine binding motif was foimd, known as the phosphotyrosine binding domain (PTB) (review Van Geer and Pawson, 1995, Sudol, 1998). In the following, the principles of the SH2-phosphoty-rosine interaction will be described, based on the SH2 domains of class lA and class 3. 

Fig. 8.20. Modular composition of adaptor proteins. Adaptor proteins do not show any enzyme activity of their own, but rather they contain protein modules which help to bind signal proteins into signal pathways. IRS-1 insulin receptor substrate 1 PTB phosphotyrosine binding domain PH pleckstrin homology domain P phosphotyrosine-containing binding site for SH2 or PTB domains HLH helrx-loop-hehx DNA binding motif...

The insulin receptor substrate IRS couples the insulin receptor to sequential effector molecules (review Ogawa et al., 1998). On binding of insulin to the insulin receptor, the tyrosine kinase activity of the receptor is stimulated. The IRS protein is phosphory-lated at several Tyr residues, which then serve as attachment points for sequential effector molecules as e.g. the Grb2-mSos complex, the P13-kinase and the protein tyrosine phosphatase SHP-2. The IRS protein also has a phosphotyrosine binding domain and a PH domain. Both modules are required for signal transduction in vivo. It is assumed that the PTB domain binds to autophosphorylation sites of the insulin receptor and that the PH domain is involved in membrane association of IRS. 

In the other pathway, an additional adaptor protein, the She protein (see 8.5), is involved in the signal transduction. The She protein has a phosphotyrosine binding domain (PTB domain) and specifically binds via this domain to autophosphorylated receptors such as the PDGF receptor and the EGF receptor. The She protein is phos-phorylated itself in the process. The phosphotyrosine residues may also serve as attachment points for the SH2 domain of Grb2 protein, whereby the Grb2-Sos complex is attached to the membrane. 

PTB domains (phosphotyrosine-binding domains) also bind (P)-Tyr in partner proteins, but their critical sequences and three-dimensional structures distinguish them from SH2 domains. The human genome encodes 24 proteins that contain PTB domains, including IRS-1, which we have already met in its role as a scaffold protein in insulin-signal transduction (Fig. 12-6). 

Since PTB domains adopt the same fold as PH domains, J. Schlessinger has suggested that the PTB domain may be another class of PH domain, a relationship that was overlooked because of the absence of sequence homologies.52 This classification is supported by differences between PTB domains and classical SH2 domains. The crystal structure of the phosphotyrosine-binding domain (PTB) of a human, neuron-specific peptide (XI1) that contains a C-terminal PTB domain, provides relevant information.53 With its PTB domain, this peptide binds to the cytoplasmic domain of the p-amyloid precursor protein (P-APP), found in the brain of patients with Alzheimer s disease. The domain with which the peptide interacts is an internalization motif of P-APP (Fig. 3.4). 

There are two major insulin receptor substrates, IRS-1 and IRS-2. IRS-1 has a (pleckstrin-like) homology domain, IHl and a phosphotyrosine-binding domain, IH2PTB. IH2P binds to the activated, phosphorylated insulin receptor in a juxta-membrane region, where the crucial phosphotyrosyl residue 960 is located. (The crystal structure of the TH2 domain, alone and complexed with the juxtamembrane region of the insulin receptor, has been solved. )... 

Yaffe MB. Phosphotyrosine-binding domains in signal transduction. Nat. Rev. Mol. Cell Biol. 2002 3 177-186. 

Videlock, E. J., Chung, V. K., Mohan, M. A., Strok, T. M., Austin, D. J. (2004). Two-dimensional diversity screening human cDNA phage display libraries with a random diversity probe for the display cloning of phosphotyrosine binding domains. 

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