PROSITE documentation PDOC00907
Phosphotyrosine interaction domain (PID) profile


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.

Expert(s) to contact by email:

Bork P.
Margolis B.

Last update:

January 2005 / Text revised.


Technical section

PROSITE method (with tools and information) covered by this documentation:

PID, PS01179; Phosphotyrosine interaction domain (PID) profile  (MATRIX)


1AuthorsUhlik M.T. Temple B. Bencharit S. Kimple A.J. Siderovski D.P. Johnson G.L.
TitleStructural and evolutionary division of phosphotyrosine binding (PTB) domains.
SourceJ. Mol. Biol. 345:1-20(2005).
PubMed ID15567406

2AuthorsBork P. Margolis B.
TitleA phosphotyrosine interaction domain.
SourceCell 80:693-694(1995).
PubMed ID7534213

3AuthorsKavanaugh W.M. Williams L.T.
TitleAn alternative to SH2 domains for binding tyrosine-phosphorylated proteins.
SourceScience 266:1862-1865(1994).
PubMed ID7527937

4AuthorsBlaikie P. Immanuel D. Wu J. Li N. Yajnik V. Margolis B.
TitleA region in Shc distinct from the SH2 domain can bind tyrosine-phosphorylated growth factor receptors.
SourceJ. Biol. Chem. 269:32031-32034(1994).
PubMed ID7798194

5AuthorsStolt P.C. Jeon H. Song H.K. Herz J. Eck M.J. Blacklow S.C.
TitleOrigins of peptide selectivity and phosphoinositide binding revealed by structures of disabled-1 PTB domain complexes.
SourceStructure 11:569-579(2003).
PubMed ID12737822

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