Src homology 2 (SH2) domains naturally bind peptide sequences on proteins/ligands bearing a phosphorylated tyrosine residue.1
SH2 domains are protein modules (of ~100 amino acids) found in many proteins involved in tyrosine kinase signalling cascades. SH2 domain ligands are tyrosine-phosphorylated sequences in specific protein targets 1.
Sadowski et al., in 1986 reported the discovery of the non-catalytic SH2 domain conserved among cytoplasmic protein tyrosine kinases 2.
Thermodynamic measurements, structural determinations, and molecular computations were applied to a series of peptide ligands of the pp60(c-src) and SH2 domain in an attempt to understand the critical binding determinants for this class of molecules. Isothermal titration calorimetry (ITC) measurements were combined with structural data derived from X-ray crystallographic studies on 12 peptide-SH2 domain complexes. The peptide ligands studied fall into two general classes: (1) dipeptides of the general framework N-acetylphosphotyrosine (or phosphotyrosine replacement)-Glu or methionine (or S-methylcysteine)-X, where X represents a hydrophobic amine, and (2) tetra- or pentapeptides of the general framework N-acetylphosphotyrosine-Glu-Glu-Ile-X, where X represents either Glu, Gln, or NH2. Dipeptide analogs which featured X as either hexanolamine or heptanolamine were able to pick up new hydrogen bonds involving their hydroxyl groups within a predominantly lipophilic surface cavity. However, due to internal strain as well as the solvent accessibility of the new hydrogen bonds formed, no net increase in binding affinity was observed 3.
Mode of Action
SH2 domains are protein modules of approx 100 amino acids that recognize and bind to specific phosphotyrosine-containing polypeptide sequences. SH2 domains are recruited to tyrosine-phosphorylated proteins in their normal physiological setting; however, short synthetic phosphopeptides derived from these cellular docking sites contain all of the necessary binding determinants to interact with SH2 domains. This fact has allowed the identification of SH2 binding sites on tyrosine-phosphorylated proteins based on the analysis of SH2 domains interacting with phosphopeptides. Structural and functional characterization of these interactions has led to the observation that a central phosphotyrosine (pY) residue is the defining feature of ligands recognized by all SH2 domains; however, specific binding of a particular SH2 domain to a tyrosine-phosphorylated protein is dependent on the primary sequence in the immediate vicinity of the pY residue, particularly the flanking sequence immediately C-terminal to the pY residue 4.
SH2 domains occur widely in eukaryotic organisms and perform an essential role in mediating protein-protein interactions within biochemical signalling networks. The widespread occurrence of SH2 in nature with variable ligand specificities suggests that these are ideal modules for evolution, as well as for mapping their roles in biochemical networks 4.
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