phosphotyrosinebinding

Phosphotyrosine binding refers to the specific recognition of phosphorylated tyrosine residues on proteins by modular protein domains. This recognition is central to many intracellular signaling pathways triggered by receptor and non-receptor tyrosine kinases. The best-characterized phosphotyrosine-binding modules are SH2 (Src homology 2) domains and phosphotyrosine-binding (PTB) domains, which recruit signaling proteins to tyrosine-phosphorylated sites and help assemble signaling complexes.

SH2 domains are approximately 100 amino acids long and contain a conserved pocket that binds the phosphate group of a phosphotyrosine. A basic residue, typically an arginine, forms a salt bridge with the phosphate, while additional contacts with residues C-terminal to the phosphotyrosine determine motif preference. Binding is usually transient and reversible, with affinities in the low micromolar to high nanomolar range, allowing dynamic signaling control.

PTB domains are structurally distinct from SH2 domains and recognize specific motif contexts around phosphotyrosines; many PTB domains bind NPXpY sequences, but some can bind phosphotyrosine directly regardless of surrounding residues. PTB-containing adapters include Shc and IRS family proteins, which link activated receptors to downstream pathways by presenting pY motifs to SH2-containing partners.

In cells, phosphotyrosine binding links receptor activation to downstream signaling cascades such as the Ras–MAPK and PI3K–Akt pathways, or modulates receptor endocytosis. Dysregulation of phosphotyrosine recognition is implicated in cancer and immune disorders. Therapeutic approaches include designing inhibitors or mimetics that disrupt SH2- or PTB-mediated interactions, aiming to dampen aberrant signaling.