Download MendeleyDimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation.
Lecointre, C., Simon, V., Kerneur, C., Allemand, F., Fournet, A., Montarras, I., Pons, J.L., Gelin, M., Brignatz, C., Urbach, S., Labesse, G., Roche, S.(2018) Structure 26: 545-554.e4
- PubMed: 29503074
- DOI: https://doi.org/10.1016/j.str.2018.01.017
- Primary Citation of Related Structures:
6EWX - PubMed 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.
Organizational Affiliation:
CRBM, "Equipe Labellisée Ligue Contre le Cancer", Univ Montpellier, CNRS, 34000 Montpellier, France.
