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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Crystallography
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Enzyme Activation
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Escherichia coli / genetics
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Humans
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Intracellular Signaling Peptides and Proteins
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Molecular Sequence Data
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Phosphoproteins / metabolism
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Protein Conformation
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / chemistry*
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Protein Tyrosine Phosphatases / metabolism*
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Sequence Homology, Amino Acid
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Substrate Specificity
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src Homology Domains / physiology
Substances
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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SH2 Domain-Containing Protein Tyrosine Phosphatases