[HTML][HTML] Crystal structure of the tyrosine phosphatase SHP-2

P Hof, S Pluskey, S Dhe-Paganon, MJ Eck… - Cell, 1998 - cell.com
P Hof, S Pluskey, S Dhe-Paganon, MJ Eck, SE Shoelson
Cell, 1998cell.com
The structure of the SHP-2 tyrosine phosphatase, determined at 2.0 Å 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 …
Abstract
The structure of the SHP-2 tyrosine phosphatase, determined at 2.0 Å 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.
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