Binding Specificity and Structure of SH2 Domains

The current structural information on SH2-substrate complexes, the results of binding experiments using peptide libraries and the systematic investigation of binding sites for different SH2 domains showed that the SH2 domains can be divided into at least five classes (lA, IB, 2, 3, 4), differing in the sequence requirements of the substrate 

The crystal structures of the SH2 domains of Src tyrosine kinase and Lck tyrosine kinase in complex with Tyr phosphorylated peptides have enabled important insight to be obtained into recognition of the phosphotyrosine residue and the neighboring amino acids in class lA of SH2 domains. The phosphate residue is boimd in a deep pocket of the SH2 domain, at the end of which an invariant Arg residue (Arg PB5) is located which contacts the negatively charged phosphate by a two-pronged interaction. It can be estimated that a phosphoserine or phosphothreonine residue would be too short to enter into a similar interaction with the Arg residue. 

The neighboring sequences of the phosphotyrosine residue are decisive for binding specificity of a SH2 domain. At this point, the structure shows that particularly the isoleucine residue at position +3 relative to phosphotyrosine is bound in a very specific manner in a pocket of the SH2 domain (Fig. 8.11). Binding of the peptide to the SH2 domain in Src kinase has therefore been compared to binding of a two-pole plug in a complementary socket, where one of the poles is phosphotyrosine and the other is the amino acid at position +3. 

Phosphohpase Cy and protein tyrosine phosphatase Syp possess an SH2 domain of class 3. Their substrate binding site has mostly hydrophobic character. The substrate is boimd in a stretched form in a flat pit where contacts are formed to a hydrophobic sequence section of the substrate, including 5—6 amino acids on the C-terminal side of the phosphotyrosine residue. 

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