Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation

Abstract

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. 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.