SH2domain

The SH2 domain, or Src Homology 2 domain, is a small protein domain of about 100 amino acids that acts as a phosphotyrosine reader in cellular signaling. It is found in a wide range of cytoplasmic and membrane-associated signaling proteins and mediates non-catalytic protein–protein interactions by binding to phosphorylated tyrosine motifs on target proteins.

Structurally, SH2 domains fold into a compact module that forms a beta-sheet core with a characteristic phosphotyrosine-binding pocket. A conserved positively charged residue coordinates the phosphate group, enabling selective binding to phosphotyrosine-containing sequences. Specificity is influenced by residues immediately C-terminal to the phosphotyrosine, and different SH2 domains show preferences for particular sequence contexts, typically described as pY-X-X-hydrophobic, among other variations. Binding is non-covalent and reversible, and can be modulated by the surrounding domain architecture and the phosphorylation state of the target.

Functionally, SH2 domains recruit signaling proteins to activated receptor tyrosine kinases or other phosphotyrosine-bearing proteins, thereby propagating or shaping signaling cascades such as the Ras-MAPK and PI3K-Akt pathways, as well as JAK-STAT signaling in some contexts. Examples of SH2-containing proteins include Grb2, SHP2, the p85 regulatory subunit of PI3K, and various kinases and adaptor proteins. Some proteins harbor tandem SH2 domains, enabling higher-affinity interactions.

History and relevance: the name derives from studies of Src (the Src Homology), and SH2 domains are widely studied as key mediators of signal transduction. Misregulation of SH2-mediated interactions can contribute to disease, including cancer, and SH2–phosphotyrosine interactions are explored as potential therapeutic targets.