| Structural highlights
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][1] [2] [3] [4]
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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tanaka H, Katoh H, Negishi M. Pragmin, a novel effector of Rnd2 GTPase, stimulates RhoA activity. J Biol Chem. 2006 Apr 14;281(15):10355-64. PMID:16481321 doi:10.1074/jbc.M511314200
- ↑ Safari F, Murata-Kamiya N, Saito Y, Hatakeyama M. Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14938-43. PMID:21873224 doi:10.1073/pnas.1107740108
- ↑ Senda Y, Murata-Kamiya N, Hatakeyama M. C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed-forward C-terminal Src kinase activation loop that promotes cell motility. Cancer Sci. 2016 Jul;107(7):972-80. PMID:27116701 doi:10.1111/cas.12962
- ↑ Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons JL, Gelin M, Brignatz C, Urbach S, Labesse G, Roche S. Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation. Structure. 2018 Apr 3;26(4):545-554.e4. doi: 10.1016/j.str.2018.01.017. Epub 2018, Mar 1. PMID:29503074 doi:http://dx.doi.org/10.1016/j.str.2018.01.017
- ↑ Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons JL, Gelin M, Brignatz C, Urbach S, Labesse G, Roche S. Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation. Structure. 2018 Apr 3;26(4):545-554.e4. doi: 10.1016/j.str.2018.01.017. Epub 2018, Mar 1. PMID:29503074 doi:http://dx.doi.org/10.1016/j.str.2018.01.017
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