PROSITE documentation PDOC50001

Src homology 2 (SH2) domain profile

The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps [1]. Similar sequences were later found in many other intracellular signal-transducing proteins [2]. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific and strictly phosphorylation-dependent manner [3,4,5,6].

The SH2 domain has a conserved 3D structure consisting of two α helices and six to seven β-strands. The core of the domain is formed by a continuous β-meander composed of two connected β-sheets [7].

So far, SH2 domains have been identified in the following proteins:

• Many vertebrate, invertebrate and retroviral cytoplasmic (non-receptor) protein tyrosine kinases. In particular in the Src, Abl, Bkt, Csk and ZAP70 families of kinases.
• Mammalian phosphatidylinositol-specific phospholipase C γ-1 and -2. Two copies of the SH2 domain are found in those proteins in between the catalytic 'X-' and 'Y-boxes' (see <PDOC50007>).
• Mammalian phosphatidyl inositol 3-kinase regulatory p85 subunit.
• Some vertebrate and invertebrate protein-tyrosine phosphatases.
• Mammalian Ras GTPase-activating protein (GAP).
• Adaptor proteins mediating binding of guanine nucleotide exchange factors to growth factor receptors: vertebrate GRB2, Caenorhabditis elegans sem-5 and Drosophila DRK.
• Mammalian Vav oncoprotein, a guanine-nucleotide exchange factor of the CDC24 family.
• Miscellanous proteins interacting with vertebrate receptor protein tyrosine kinases: oncoprotein Crk, mammalian cytoplasmic proteins Nck, Shc.
• STAT proteins (signal transducers and activators of transcription).
• Chicken tensin.
• Yeast transcriptional control protein SPT6.

The profile developed to detect SH2 domains is based on a structural alignment consisting of 8 gap-free blocks and 7 linker regions totaling 92 match positions.