PTB, a protein-protein interaction domain important for signal transduction

Protein-protein interaction domains play a crucial role in the signal transduction of receptors with tyrosine kinase activity (RTKs). SH2 domains have been shown to bind tyrosine-phosphorylated peptides with a specificity determined by residues lying carboxyterminal to the phosphotyrosine. Recently, a second phosphotyrosine interacting domain has been characterized by several groups and named PTB (phosphotyrosine binding) or (phosphotyrosine interaction) domain. The binding specificity of this new domains is determined by residues amino-terminal to the phosphotyrosine. The binding site of SHC and IRS-1 proteins PTB domains, two major substrates of RTKs, is represented by the sequence Psi XNPpY (where Psi is a hydrophobic residue, N is asparagine, P is proline, X is any amino acid and pY is phosphotyrosine). The integrity of this domain seems important for the signaling through RTKs such as epidermal growth factor- and insulin-receptors. From structural analysis, PTB domains are proposed to belong to the family of PH (pleckstrin homology) domains. Through computer alignments, several putative PTB domains have been detected in other cytoplasmic proteins. Among them, FE65 and X11 have been shown to contact beta APP (beta amyloid precursor protein) with their PTB domain. Whereas the overall structure and binding properties of these domains seem similar to those of the SHC PTB domain, they differ in the sense that tyrosine phosphorylation of the target (Psi XNPXY) is not required. The interaction between beta APP and FE65/X11 is discussed in relation to their potential role in the processing of beta APP, a major actor is Alzheimer's disease. Morever, the presence of Psi XNPXY motifs in several membrane proteins (integrins, LDL receptor) leads to the hypothesis that other PTB domain-containing proteins may contact these receptors and participate to their metabolism and functions.