Proteins encoding phosphotyrosine binding (PTB) domains function as adaptors or scaffolds to organize the signaling complexes involved in wide-ranging physiological processes including neural development, immunity, tissue homeostasis and cell growth. Due to structural differences, PTB domains are divided into three groups represented by phosphotyrosine-dependent IRS-like (see <PDOC51064>), phosphotyrosine-dependent Shc-like, and phosphotyrosine-independent Dab-like PTBs. The last two PTBs have been named as phosphotyrosine interaction domain (PID or PI domain). PID domain has an average length of about 160 amino acids [1].

The Shc-like PID specifically binds to the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins including growth factor receptors. On the other hand the Dab-like PID domain binds to non-phosphorylated tyrosine residue or even a phenylalanine at the same position [2]. Most of the ligands for Shc-like PID domains are RTK or cytokine, whereas phosphotyrosine independent Dab-like PID domains seems to mediate other types of signaling pathways, like endocytosis/processing or exocytosis. This domain binds both peptides and headgroups of phosphatidylinositides, utilizing two distinct binding motifs to mediate spatial organization and localization within cells [1,2,3,4].

The 3D structure of PID domain has been solved (see <PDB:1NTV>) [5]. It shares a folding pattern, commonly referred to as the PH-domain "superfold". The core "superfold" consists of seven antiparallel β strands forming two orthogonal β sheets. This β sandwich is capped at the C terminus by an α helix. It contains a peptide binding pocket (formed by the β strand 5 and C-terminal α helix) and a highly basic phospholipid binding "crown" (largely composed of residues from loop regions near the N terminus). Both Shc and Dab1 have two additional α helices, one of which is located at the N terminus and the other between β 1 and β 2 strands.

PID has also been found in the proteins listed below.

• Mammalian Shc transforming protein which contains one N-terminal PID and a C-terminal SH2 domain (see <PDOC50001>).
• Human Shc-related protein Sck that shares the same modular architecture.
• Mammalian protein X11 which is expressed prominently in the nervous system. It contains 2 disc homologous regions (DHR) downstream of the PID.
• Rat FE65, a transcription-factor activator expressed preferentially in liver. The presence of a WW domain (see <PDOC50020>) as well as 2 PIDs indicate a possible role in signal transduction.
• Drosophila nuclear Numb protein, which is required in determination of cell fate during sensory organ formation in Drosophila embryos. It has one PID.
• Drosophila protein disabled (gene dab), which is involved in embryonic neural development. This cytoplasmic, tyrosine phosphorylated protein is found in CNS axons and body wall muscles. It contains one N-terminal PID.
• Mouse mitogen-responsive phosphoprotein P96 and the human homolog, DOC-2. They possess one N-terminal PID.
• Mammalian regulator of G-protein signalling 12 (RGS12).
• Caenorhabditis elegans hypothetical protein F56D2.1 which contains an N-terminal insulinase-type domain (see <PDOC00130>) followed by a PID.

The profile we developed covers the entire PID domain.