Dimerization 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.

doi:10.1101/218669

bioRxiv · 10.1101/218669

Dimerization 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.

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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 906-1368 amino acids C-terminus, which encompasses its kinase domain. We show that Pragmin contains a classical protein kinase fold devoid of catalytic activity. A particular inhibitory triad, conserved in a Pragmin/SgK269/PEAK1/C19orf35 superfamily, tightly holds the catalytic lysine (K997) to prevent ATP binding. 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 bordered 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. Thus, our results reveal a new dimerization mechanism by which a pseudo-kinase can induce protein tyrosine phosphorylation.

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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.. 2017-11-27. Dimerization of the Pragmin pseudo-kinase regulates protein tyrosine phosphorylation. https://doi.org/10.1101/218669

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