SH2domän

SH2-domain, or SH2 domain, is a protein domain found in a wide range of intracellular signaling proteins. It is of about 100 amino acids in length and specializes in recognizing phosphotyrosine-containing sequences, enabling proteins to be recruited to activated receptors or kinases. The domain’s binding is dependent on the presence of a phosphorylated tyrosine within a peptide motif and is influenced by residues adjacent to the phosphotyrosine.

Structurally, the SH2 domain adopts a fold consisting of a central beta-sheet flanked by alpha helices. The phosphotyrosine binding pocket is formed by conserved residues, including an arginine that coordinates the phosphate group. Specificity for different ligands is mainly determined by the residues C-terminal to the phosphotyrosine, particularly the +1 to +5 positions, which shape the pocket and interactions with the target peptide.

Functionally, SH2 domains act as modular interaction modules that mediate protein–protein interactions in signal transduction. By binding to phosphotyrosine motifs on activated receptors or adaptor proteins, SH2-containing proteins are recruited to signaling complexes, enabling downstream pathways such as MAPK, PI3K, and JAK/STAT to be activated or modulated.

Distribution and examples: SH2 domains are widespread in eukaryotes and are found in many signaling adapters and phosphatases, including Grb2, SHC, and SHP2. Although highly specific for phosphotyrosine ligands, some SH2 domains exhibit noncanonical or context-dependent binding.

History: The name derives from Src Homology 2, a term originating from studies of the Src family of oncoproteins in the 1980s, where this domain was first characterized.