6ewx | pdb_00006ewx

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

spinqualitylabelsall models 6ewx, resolution 2.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ewx is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.771Å Ligands: SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PRAG1_RAT Catalytically inactive protein kinase that acts as a scaffold protein (PubMed:29503074). Functions as an effector of the small GTPase RND2, which stimulates RhoA activity and inhibits NGF-induced neurite outgrowth (PubMed:16481321). Promotes Src family kinase (SFK) signallig by regulating the subcellular localization of CSK, a negative regulator of these kinases, leading to the regulation of cell morphology and motility by a CSK-dependent mechanism (PubMed:27116701, PubMed:21873224). Acts as a critical coactivator of Notch signaling (By similarity).[UniProtKB:Q571I4] Publication Abstract from PubMed 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. 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 Apr 3;26(4):545-554.e4. doi: 10.1016/j.str.2018.01.017. Epub 2018, Mar 1. PMID:29503074 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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