SH2 domain

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File:1lkkA SH2 domain.png
Ribbon diagram of the SH2 domain of human P56-Lck tyrosine kinase (PDB accession code 1LKK, chain A), colored from blue (N-terminus) to red (C-terminus).

The Src homology 2 domain (or SH2 domain) is a protein domain of about 100 amino acid residues first identified as a conserved sequence region among the oncoproteins Src and Fps.

Similar sequences were later found in many other intracellular proteins involved in signal transduction, such as Abl, ZAP70, STAT proteins,Grb2, and RasGAP.

Binding and phosphorylation

SH2 domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target proteins, and SH2 domains represent the largest class of known pTyr-recognition domains[1].

Phosphorylation of tyrosine residues in a protein occurs during signal transduction and is carried out by tyrosine kinases. In this way, phosphorylation of a substrate by tyrosine kinases acts as a switch to trigger binding to an SH2 domain-containing protein. The intimate relationship between tyrosine kinases and SH2 domains is supported by their coordinate emergence during eukaryotic evolution.


SH2 domains are not present in yeast and appear at the boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum[2].

A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 110 proteins encoded by the human genome[3], representing a rapid rate of evolutionary expansion among the SH2 domains.

A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mouse.[4]

Proteins with SH2 domains include:


Many biological signaling proteins use this mode of regulated protein-protein interactions as a means to localize proteins to various sub-cellular compartments, control enzymatic activities of proteins as well as nucleate multiprotein complexes, to name a few.

The SH2 domain has thus become a prototype for a large number of modular interaction domains that have been since identified.

The discovery of the SH2 domain and its many roles in signal transduction introduced the critical concept of how biology has exploited the use of modular interaction domains to create complex signaling networks.


  1. Pawson, T., Gish, G., Nash, P. (2001). SH2 domains, interaction modules and cellular wiring. Trends in Cell Biology 11(12): 504-511.
  2. Eichinger, L. et al. (2005). The genome of the social amoeba Dictyostelium discoideum. Nature 435, 43-57.
  3. Liu et al. (2006), The Human and Mouse Complement of SH2 Domain Proteins – establishing the boundaries of phosphotyrosine signaling. Molecular Cell 22: 851-868.

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