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Structure. 2018 Apr 3;26(4):545-554.e4. doi: 10.1016/j.str.2018.01.017. Epub 2018 Mar 1.

Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation.

Author information

1
CRBM, "Equipe Labellisée Ligue Contre le Cancer", Univ Montpellier, CNRS, 34000 Montpellier, France.
2
CBS, Univ Montpellier, CNRS, INSERM, 34090 Montpellier, France.
3
IGF, Univ Montpellier, CNRS, INSERM, 34090 Montpellier, France.
4
CBS, Univ Montpellier, CNRS, INSERM, 34090 Montpellier, France. Electronic address: gilles.labesse@cbs.cnrs.fr.
5
CRBM, "Equipe Labellisée Ligue Contre le Cancer", Univ Montpellier, CNRS, 34000 Montpellier, France. Electronic address: serge.roche@crbm.cnrs.fr.

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.

KEYWORDS:

CSK; cancer; cell adhesion; protein tyrosine phosphorylation; pseudo-kinase; signaling

Comment in

PMID:
29503074
DOI:
10.1016/j.str.2018.01.017
[Indexed for MEDLINE]
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