6EWX

Structure of Pragmin pseudo-kinase reveals a dimerization mechanism to regulate protein tyrosine phosphorylation and nuclear transcription

Summary for 6EWX

• Entry DOI: 10.2210/pdb6ewx/pdb
• Descriptor: PEAK1-related kinase-activating pseudokinase 1, SULFATE ION (3 entities in total)
• Functional Keywords: pseudokinase, cancer, scaffolding protein, cell invasion
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 2
• Total formula weight: 107921.55

Authors

Gelin, M.,Allemand, F.,Fournet, A.,Labesse, G. (deposition date: 2017-11-06, release date: 2018-01-31, Last modification date: 2024-05-08)

Primary citation

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.
Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation.
Structure, 26:545-554.e4, 2018

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.

PubMed: 29503074
DOI: 10.1016/j.str.2018.01.017

Experimental method

X-RAY DIFFRACTION (2.771 Å)