Figure 1

Structure and sequence patterns of the SH2 domain. (A) Structure of the v-Src SH2 domain in complex with the pYEEI peptide (PDB ID: 1SPS). The two conserved α-helices are coloured green, and the seven β-strands are coloured orange. The peptide is shown as grey sticks. The phosphate group of pTyr binds to Arg175 located on the βB strand of the SH2 domain. The pTyr+3 Ile side chain is captured by a hydrophobic pocket provided between the EF and BG loops. (B) Conservation and variation in the secondary structural elements of SH2 domains based on experimentally determined structures. Refer to [40] for a list of SH2 domain structures. The N-terminal half of an SH2 domain is dedicated to pTyr recognition and is much less variable than the C-terminal half where the specificity pocket is located. A dashed line indicates that the element does not exist in an SH2 domain. Structural variations are observed more often in the C-terminal half. For example, the BG loop of the STAP family (BRDG1 & BKS) and the Cbl family SH2 domains are much shorter than in other SH2 domains, which results in an open pocket capable of binding a hydrophobic pTyr +4 residue [40, 43]. Pro287 of the ITK SH2 domain is susceptible to cis trans isomerization via its CD loop, which leads to a switch of binding partners [44–46]. The long, proline-rich DE loop insertion in the Crk SH2 domain is the binding site for the Abl SH3 domain [47]. (C) The tandem SH2 domains of the transcription factor Spt6. Four research groups have reported crystal and solution structures, which are essentially identical to each other [48–51]. Shown here is the crystal structure of the Saccharomyces cerevisiae Spt6 with a sulfate ion located in the "canonical" phospho-residue binding pocket of the N-terminal SH2 domain (PDB ID: 3PSK) [48]. Mutagenesis studies and NMR titration analysis suggested that this pocket, involving Arg1282, as well as a positively charged patch, including Lys1435 of the C-terminal SH2 domain (residues shown as cyan sticks), are the binding sites of the phosphorylated CTD peptides [49, 50, 52].