The ability of SH2 domains to preferentially bind to certain tyrosine phosphorylated proteins is dependent upon their capacity to discriminate between different phosphopeptides. The residues adjacent to the phosphotyrosine on either the N- or C- terminus define the specificity for a particular SH2 domain, similar to a zip code for delivering mail (Songyang and Cantley, 2004). Determining sequence specificity of these SH2 domains is an essential first step toward identifying their in vivo binding partners and understanding their physiological functions. Such information will also facilitate the development of specific SH2 domain inhibitors as potential therapeutic agents and research tools (Machida and Mayer, 2005). 

Contextual Peptide Specificity

SH2 domains recognize contextual peptide sequence information to determine selectivity.

Liu BA, Jablonowski K, Shah EE, Engelmann BW, Jones RB, Nash PD.

Mol Cell Proteomics. 2010 Nov;9(11):2391-404. Epub 2010 Jul 13.

See attachments below. 

Liu BA, Engelmann BW, Nash PD.

FEBS Letters  Volume 586, Issue 17 , Pages 2597-2605, 14 August 2012

Potential Interactome

SRC Homology 2 Domain Binding Sites in Insulin, IGF-1 and FGF receptor mediated signaling networks reveal an extensive potential interactome.

Bernard A Liu, Brett W Engelmann, Karl Jablonowski, Katherine Higginbotham, Andrew S Stergachis and Piers D Nash. 

Cell Communication and Signaling 2012, 10:27 doi:10.1186/1478-811X-10-27

SH2 Motif Search