Descriptions


SH2 domain function

Tyrosine phosphorylated regions in proteins function as specific binding sites for the SH2 domains containing cellular signalling proteins. Binding of SH2 domains to their in vivo targets recruits the SH2 domain-containing protein to its proper signalling complex and thereby initiates or regulates downstream signalling cascades (reviewed in Schlessinger and Lemmon, 2003).
In addition to their role in assembling activated complexes, particular SH2 domains also form intramolecular interactions that regulate enzyme activity. A loop from the N-terminal SH2 domain binds to the catalytic cleft of the phosphatase domain in the same SHP-2 molecule leading to an autoinhibited configuration (Hof et al., 1998). The Src SH2 domain has been shown to bind a phosphorylated tyrosine at the C-terminus of the same molecule resulting inactivation of enzyme activity by rearrangement of catalytic center in the kinase domain (reviewed in Hubbard et al., 1998). In both examples, the high affinity ligands can compete with the intramolecular interactions and release the catalytic domains for their in vivo targets.
Majority of the peptide-binding motifs for individual SH2 domains have been identified by using in vitro oriented phosphopeptide library assays (Songyang and Cantley, 1995; Songyang et al., 1993). Based on these results, together with structural analyses of different ligand-binding models, it is apparent that SH2 domains bind distinct but overlapping sequence motifs. The selectivity of an individual SH2 domain is not sharply defined, and a range of residues is typically tolerated at each site following the phosphotyrosine. Supporting these findings, different SH2 domains have been shown to compete for same binding target in vivo (e.g. Nishimura et al., 1993; Sayos et al., 2001).

SH2 domain structure

Structures of a significant number of SH2 domains both in isolation and bound to various target molecules have been determined by X-ray crystallography and NMR spectroscopy. All the analysed SH2 domains have a typical SH2 domain fold consisting of a large anti-parallel β-sheet sandwiched between two α-helices The central β-sheet divides the domain into two functionally separate sides. The αA-helix borders the face binding to phosphotyrosine. Residues from αB-helix and the EF and BG-loops are involved in binding of side chains C-terminal to phosphotyrosine in the ligand. The βD', βE and βF strands form an additional β-sheet that closes off one part of this side (Figure 2 and the notation used for describing the secondary structures).