Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation

The pseudo-kinase and signaling protein Pragmin has been linked to cancer by regulating protein tyrosine phosphorylation via unknown mechanisms. Here we present the crystal structure of the Pragmin 906–1,368 amino acid C terminus, which encompasses its kinase domain. We show that Pragmin contains a...

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Veröffentlicht in:Structure (London) 2018-04, Vol.26 (4), p.545-554.e4
Hauptverfasser: Lecointre, Céline, Simon, Valérie, Kerneur, Clément, Allemand, Frédéric, Fournet, Aurélie, Montarras, Ingrid, Pons, Jean-Luc, Gelin, Muriel, Brignatz, Constance, Urbach, Serge, Labesse, Gilles, Roche, Serge
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Sprache:eng
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Zusammenfassung:The pseudo-kinase and signaling protein Pragmin has been linked to cancer by regulating protein tyrosine phosphorylation via unknown mechanisms. Here we present the crystal structure of the Pragmin 906–1,368 amino acid C terminus, which encompasses its kinase domain. We show that Pragmin contains a classical protein-kinase fold devoid of catalytic activity, despite a conserved catalytic lysine (K997). By proteomics, we discovered that this pseudo-kinase uses the tyrosine kinase CSK to induce protein tyrosine phosphorylation in human cells. Interestingly, the protein-kinase domain is flanked by N- and C-terminal extensions forming an original dimerization domain that regulates Pragmin self-association and stimulates CSK activity. A1329E mutation in the C-terminal extension destabilizes Pragmin dimerization and reduces CSK activation. These results reveal a dimerization mechanism by which a pseudo-kinase can induce protein tyrosine phosphorylation. Further sequence-structure analysis identified an additional member (C19orf35) of the superfamily of dimeric Pragmin/SgK269/PEAK1 pseudo-kinases. [Display omitted] •Pragmin possesses a protein-kinase fold devoid of catalytic activity•N- and C-terminal kinase extensions form an original dimerization domain•Pragmin interacts with CSK to induce protein tyrosine phosphorylation•Pragmin dimerization induces CSK activation Pragmin is a pseudokinase implicated in cancer. It regulates protein tyrosine phosphorylation via unknown mechanisms. Lecointre et al. show that Pragmin possesses a protein kinase fold devoid of catalytic activity. Its N- and C-terminal extensions form a dimerization domain that induces activation of CSK kinase to induce protein tyrosine phosphorylation.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2018.01.017