Crystal Structure of the Tyrosine Phosphatase SHP-2

Abstract

The structure of the SHP-2 tyrosine phosphatase, determined at 2.0 angstroms resolution, shows how its catalytic activity is regulated by its two SH2 domains. In the absence of a tyrosine-phosphorylated binding partner, the N-terminal SH2 domain binds the phosphatase domain and directly blocks its active site. This interaction alters the structure of the N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely, interaction of the N-SH2 domain with phosphopeptide disrupts its phosphatase recognition surface. Thus, the N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. Recognition of bisphosphorylated ligands by the tandem SH2 domains is an integral element of this switch; the C-terminal SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation.

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

“…Threonine-507 (T507) of SHP-2 is highly conserved among PTPs (Andersen et al, 2001) and constitutes the surface of the catalytic cleft in the PTP domain, facing the N-SH2 domain in the basal state of SHP-2 (Hof et al, 1998) (Figures 1c and d). The lysine substitution may inhibit the autoinhibitory interaction between the N-SH2 domain and PTP domain, thereby activating the basal phosphatase activity.…”

“…The three-dimensional structure of the basal inactive form of SHP-2 was obtained through Protein Data bank code 2SHP (Hof et al, 1998) with the use of DeepView Swiss-PdbViewer 3.7 (Guex and Peitsch, 1997).…”

“…In the basal state, SHP-2 is maintained in an inactive conformation by hydrophobic interaction between the N-SH2 domain and the PTP domain. Binding of a phosphotyrosinecontaining peptide to the N-SH2 domain alleviates the autoinhibition to form an open conformation with active phosphatase activity (Hof et al, 1998;Neel et al, 2003). Most if not all mutations found in Noonan syndrome or leukemia affect residues in the N-SH2 domain or PTP domain that abolish the autoinhibitory interaction and thereby exhibit increased basal phosphatase activity (Tartaglia et al, 2003).…”

Reduced phosphatase activity of SHP‐2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1

“…The structure of wild-type (WT) SHP-2 [10] (PDB code 2shp) was loaded into the program ICM (Molsoft LLC, www.molsoft.com) and the LS-associated residues were mapped and visually inspected.…”

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

“…It consists of two tandem SH2 domains that are able to bind phosphorylated tyrosine residues, a central phosphatase domain, and a C-terminal tail carrying two tyrosine phosphorylation sites and a proline-rich sequence. In its inactive state SHP-2 assumes a closed conformation in which the N-terminal SH2 domain directly binds the phosphatase domain, thereby blocking the active site of the enzyme [1]. SHP-2 is activated by binding of its SH2 domains to phosphorylated tyrosine residues, which leads to an opening of the conformation and activation of the phosphatase function.…”