MS11-P07 Crystal structure of a mammalian pseudokinase reveals an original dimerization Gilles Labesse (Centre de Biochimie Structurale, CNRS, Montpellier, France) Céline Lecointre (Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier, France) Valérie Simon (Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier, France) Clément Kerneur (Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier, France) Frédéric Allemand (Centre de Biochimie Structurale, CNRS, Montpellier, France) Ingrid Montarras (Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier, France) Muriel Gelin (Centre de Biochimie Structurale, CNRS, Montpellier, France) Serge Urbach (Institut de Génomique Fonctionnelle, CNRS, Montpellier, France) Serge Roche (Centre de Recherche de Biologie cellulaire de Montpellier, CNRS, Montpellier, France)email: labesse@cbs.cnrs.fr

Although partially or totally devoid of any ATP binding or hydrolysis, pseudokinases are now recognized as key players in cell signaling. However, their functioning is still unclear for a number of such pseudokinases encoded in the mammalian genomes. Here we describe the crystal structure of the folded region of SGK223, a large pseudokinase from rat. We could solve the crystal structure by molecular replacement, at a 3.0 A resolution, despite a low overall sequence identity (20-25% over the whole kinase domain), using the software Phenix, an ensemble of partial models built using our server @TOME-2 and data recorded automatically on the beamline MASSIF-1 at the ESRF synchrotron.

The structure contains a classical protein kinase fold, devoid of any ATP-binding activity. It also highlighted several sequence motifs conserved in other psudokinases and extend the corresponding superfamily. Interestingly, these pseudokinases possess N- and C-terminal extensions forming an original dimerization domain. This dimeric pseudokinases have been linked to cancer by up-regulating protein tyrosine phosphorylation. Our results suggest a structural model for understanding how pseudokinases induce protein tyrosine phosphorylation [1,2].

References:

[1] Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation. Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons JL, Gelin M, Brignatz C, Urbach S, Labesse G, Roche S. Structure. 2018, 26, 545-554.

[2] A Pseudo-Kinase Double Act. Preuß F, Mathea S, Knapp S. Structure. 2018, 26, 527-528 (preview)
Keywords: cell signaling, cancer, protein-kinase