NMR backbone assignment of the mitogen-activated protein (MAP) kinase p38

Vogtherr, Martin; Saxena, Krishna; Grimme, Susanne; Betz, Marco; Schieborr, Ulrich; Pescatore, Barbara; Langer, Thomas; Schwalbe, Harald

doi:10.1007/s10858-005-2449-x

Cited by 32 publications

(37 citation statements)

References 2 publications

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“…4) (BMRB (Biological Magnetic Resonance Bank) accession number 26758). Note that similar results were previously obtained for the homologous MAP kinase p38␣ (28) for which 64% of amide signals were initially assigned using a set of selectively 15 N-labeled samples and distance information from a paramagnetic adenosine derivate. Later, the sequence-specific backbone assignment was improved to 82% (29).…”

Section: Pbm Of P38␥ Is An Efficient Inducer Of Cell Death In Human Gsupporting

confidence: 66%

Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

Maisonneuve

Caillet‐Saguy

Vaney

et al. 2016

Journal of Biological Chemistry

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The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cell death induction in neuroblastoma and glioblastoma cell lines in a PDZ⅐PDZ binding motifs-dependent manner, but the cellular partners of PTPN4 involved in cell protection are unknown. Here, we described the mitogen-activated protein kinase p38␥ as a cellular partner of PTPN4. The main contribution to the p38␥⅐PTPN4 complex formation is the tight interaction between the C terminus of p38␥ and the PDZ domain of PTPN4. We solved the crystal structure of the PDZ domain of PTPN4 bound to the p38␥ C terminus. We identified the molecular basis of recognition of the C-terminal sequence of p38␥ that displays the highest affinity among all endogenous partners of PTPN4. We showed that the p38␥ C terminus is also an efficient inducer of cell death after its intracellular delivery. In addition to recruiting the kinase, the binding of the C-terminal sequence of p38␥ to PTPN4 abolishes the catalytic autoinhibition of PTPN4 and thus activates the phosphatase, which can efficiently dephosphorylate the activation loop of p38␥. We presume that the p38␥⅐PTPN4 interaction promotes cellular signaling, preventing cell death induction. PTPN45 is a non-receptor-tyrosine phosphatase (PTP) with functions in T cell signaling, learning, spatial memory, and cerebellar synaptic plasticity (1-3). Its overexpression reduces cell proliferation in COS-7 cells and suppresses CrkI-mediated cell growth and mobility in HEK293T cells (4, 5). PTPN4 also regulates neuronal cell homeostasis by protecting neurons against apoptosis (5, 6). PTPN4 is a large modular protein containing three domains, an N-terminal FERM domain, a PDZ domain, and a C-terminal catalytic tyrosine phosphatase domain (7). PDZ domains are protein-protein interaction domains, which play a central role in cell signaling by favoring spatial contacts between enzymes and their substrates or, more generally, by assembling and/or regulating protein networks (8, 9). Thus, disrupting the interactions between PDZ domains and PDZ binding motifs (PBM) can trigger profound alterations in cell signaling pathways (10 -12). Such disruptions of PDZ⅐PBM complexes are used by viruses to hijack cell signaling pathways to their own advantage and can also be obtained by treating cells with an excess of cell penetrating peptide encoding a PBM (13). Indeed, we showed that rabies virus (RABV) peptides encoding a PBM can target the PDZ domain of PTPN4 (PTPN4-PDZ) and antagonize the function of PTPN4, leading to cell death (6). We optimized such pro-apoptotic peptides and designed the Cyto8-RETEV sequence, that is so far the most affine ligand of PTPN4-PDZ and the best inducer of cell death (15).Four endogenous partners of PTPN4 have been reported: the glutamate receptor ␦2 and ⑀ subunits, the T-cell receptor subunit, the CrkI oncoprotein, and the TRIF (TIR domain-containing adaptor-inducing interferon-B)-related adaptor molecule TRAM (3,5,16,17). Nevertheless, the natural ligands of PTPN4 involved in the regulation of cell homeos...

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Section: Pbm Of P38␥ Is An Efficient Inducer Of Cell Death In Human Gsupporting

confidence: 66%

Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

Maisonneuve

Caillet‐Saguy

Vaney

et al. 2016

Journal of Biological Chemistry

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“…PTP1b 1ECV [18] 1PTY [19] T151S C215S D252E 5474 [20] PKA 1YDR [21] 1CMK [22] M6K Y69F F108Y A124P 6183 [23] p38 1A9U [24] 1P38 [25] L48H T26A 6468 [26] lecular van der Waals energy and the experimental AIR energy showed strong correlations of similar size for different proteinligand systems. They are therefore suitable as measurements of accuracy.…”

Section: Mutations Bmrb Codementioning

confidence: 93%

How Much NMR Data Is Required To Determine a Protein–Ligand Complex Structure?

et al. 2005

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Here we present an NMR-based approach to solving protein-ligand structures. The procedure is guided by biophysical, biochemical, or knowledge-based data. The structures are mainly derived from ligand-induced chemical-shift perturbations (CSP) induced in the resonances of the protein and ligand-detected saturated transfer difference signals between ligands and selectively labeled proteins (SOS-NMR). Accuracy, as judged by comparison with X-ray results, depends on the nature and completeness of the experimental data. An experimental protocol is proposed that starts with calculations that make use of readily available chemical-shift perturbations as experimental constraints. If necessary, more sophisticated experimental results have to be added to improve the accuracy of the protein-ligand complex structure. The criteria for evaluation and selection of meaningful complex structures are discussed. These are exemplified for three complexes, and we show that the approach bridges the gap between theoretical docking approaches and complex NMR schemes for determining protein-ligand complexes; especially for relatively weak binders that do not lead to intermolecular NOEs.

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“…The NMR assignment of p38 [10] is incomplete. Spectra of uniformly 15 N-labeled p38 gives amide signals of only 254 (75 %) out of 337 expected signals, 216 (85 %) of which could be assigned.…”

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confidence: 99%

NMR Characterization of Kinase p38 Dynamics in Free and Ligand‐Bound Forms

et al. 2006

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In its apo state kinase p38 effects slow motions that can be detected in the NMR spectrum. One of the affected parts is the pharmacologically interesting DFG motif. Diarylurea inhibitors that bind to the DFG‐out conformation lock this motif in a defined state, whereas DFG‐in inhibitors that bind to the adjacent hinge region leave the flexibility of the DFG motif unaffected (see crystal structure of the complex of p38 with the inhibitor SB203580).

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NMR backbone assignment of the mitogen-activated protein (MAP) kinase p38

Cited by 32 publications

References 2 publications

Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

How Much NMR Data Is Required To Determine a Protein–Ligand Complex Structure?

NMR Characterization of Kinase p38 Dynamics in Free and Ligand‐Bound Forms

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