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41.
Patricia Santofimia-Castaño Bruno Rizzuti Olga Abián Adrián Velázquez-Campoy Juan L. Iovanna José L. Neira 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(6):1283-1295
Background
NUPR1 is a multifunctional intrinsically disordered protein (IDP) involved, among other functions, in chromatin remodelling, and development of pancreatic ductal adenocarcinoma (PDAC). It interacts with several biomolecules through hydrophobic patches around residues Ala33 and Thr68. The drug trifluoperazine (TFP), which hampers PDAC development in xenografted mice, also binds to those regions. Because of the large size of the hot-spot interface of NUPR1, small molecules could not be adequate to modulate its functions.Methods
We explored how amphipathic helical-designed peptides were capable of interacting with wild-type NUPR1 and the Thr68Gln mutant, inhibiting the interaction with NUPR1 protein partners. We used in vitro biophysical techniques (fluorescence, circular dichroism (CD), nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC)), in silico studies (docking and molecular dynamics (MD)), and in cellulo protein ligation assays (PLAs) to study the interaction.Results
Peptide dissociation constants towards wild-type NUPR1 were ~ 3?μM, whereas no interaction was observed with the Thr68Gln mutant. Peptides interacted with wild-type NUPR1 residues around Ala33 and residues at the C terminus, as shown by NMR. The computational results clarified the main determinants of the interactions, providing a mechanism for the ligand-capture that explains why peptide binding was not observed for Thr68Gln mutant. Finally, the in cellulo assays indicated that two out of four peptides inhibited the interaction of NUPR1 with the C-terminal region of the Polycomb RING protein 1 (C-RING1B).Conclusions
Designed peptides can be used as lead compounds to inhibit NUPR1 interactions.General significance
Peptides may be exploited as drugs to target IDPs. 相似文献42.
One to 10 μM trifluoperazine was found to potentiate luminol-dependent chemiluminescence of neutrophils induced by n-formyl-methionyl-leucylphenyalanine. It did not potentiate chemiluminescence induced by A23187 or by phobor myristate acetate. Low concentrations of another calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, an intracellular Ca++ antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate, and a local anesthetic dibucaine, were found to possess similar activity. It is suggested that trifluoperazine potentiates chemiluminescence by acting on certain cellular processes that follow after stimulation by n-formyl-methionyl-leucylphenylalanine, but not by A23187 or by phorbor myristate acetate, and that this effect may be calmodulin-independent. 相似文献
43.
Evidence that a Ca2+ chelator and a calmodulin blocker interfere with the structure of inter-Sertoli junctions 总被引:1,自引:0,他引:1
Ca2+ dependence of tight junction structure has been well documented in cultured epithelial tissues, and regulatory mechanisms have been identified. To analyse the possible control exerted on inter-Sertoli junctions, we exposed guinea-pig seminiferous tubules to the presence of a Ca2+ chelator (EGTA) and to a calmodulin blocker (Trifluoperazine, TFP) in vitro, for times ranging from 30 to 120 min. We observed the morphology of junctional complexes and the basal cytoplasmic regions in sections and replicas. Sertoli cell response to Ca2+ depletion involved several events: retraction of cells toward the base of the tubule and a consequent stretching of the points of fusion, augmented density of the cytoplasm, and destabilization of the array of intramembrane particles. Exposure of tubules to TFP resulted in disruption of the interactions between actin filaments and membrane junctional specialization, as well as a disorganization of other cytoskeletal elements. Thus, in vitro, junction integrity appears to be related to Ca2+ level, and Ca2+ depletion apparently interferes with Ca2+ distribution inside the cell and on microfilaments involved in junction regulation. Our results do not provide direct evidence for any particular mechanism of action of TFP, but a multiple effect is evident. TFP, which affects Ca2+ regulation and membrane fluidity, probably acts indirectly on junction-associated filaments. Both the experimental conditions tested suggest a Ca2+-mediated regulatory role of microfilaments of this complex junction. 相似文献
44.
A model for human cardiac troponin C and for modulation of its Ca2+ affinity by drugs 总被引:1,自引:0,他引:1
Calcium sensitizers are drugs which increase force development in striated muscle by sensitizing myofilaments to Ca2+. This can happen by increasing Ca2+ affinity of the regulatory domain of Ca2+ binding protein troponin C. High resolution crystal structures of two calcium binding proteins, calmodulin (Babu et al.: J. Mol. Biol. 203:191-204, 1988) and skeletal troponin C (Satyshur et al.: J. Biol. Chem. 263:1628-1647, 1988; Herzber et al.: J. Mol. Biol. 203:761-779, 1988), have recently been published. This makes it possible to model in detail the calcium-sensitizing action of drugs on troponin C. In this study a model of human cardiac troponin C in three-calcium state has been constructed. When calcium is bound to calcium site II of cardiac troponin C an open conformation of the protein results, which has a hydrophobic pocket surrounded by a few polar side chains. Complexation of three drugs, trifluoperazine, bepridil, and pimobendan, to the hydrophobic pocket is studied using energy minimization techniques. Two different binding modes are found, which differ in the location of a strong electrostatic interaction. In analogy with the crystal structure of skeletal troponin C it is hypothezed that in cardiac troponin C an interaction occurs between Gln-50 and Asp-88, which has a long-range effect on calcium binding. The binding modes of drugs, where a strong interaction with Asp-88 exists, can effectively prevent the interaction between Asp-88 and Gln-50 in the protein, and are proposed to be responsible for the calcium-sensitizing properties of the studied drugs. 相似文献
45.
Tudor H. Thomas 《Plant Growth Regulation》1995,16(3):299-303
Growth of carrot and radish seedlings in nutrient culture was inhibited by pretreatment with three calmodulin inhibitors. There was little selective effect on specific organs, shoots, tap root and fibrous roots over a range of concentrations. Although pretreatment with CaCl2 (0.5 mM) did not affect growth of untreated seedlings, it partially reduced the inhibitory effects of trifluoperazine over the concentration range 0.01–0.05 mM. Trifluoperazine reduced the growth of GA3-treated seedlings but did not overcome the modifying effect of GA3 in favouring shoot/root ratio; ABA exacerbated its inhibitory effect on overall seedling growth and particularly on tap root development.Abbreviations GA3
gibberellic acid
- ABA
abscisic acid
- CaCl2
calcium chloride
- GAs
gibberellins
- Tfp
trifluoperazine 相似文献
46.
K Nakashima S Fujii K Kaku T Kaneko 《Biochemical and biophysical research communications》1982,104(1):285-289
In the red cell incubated with ortho-[32P] phosphate, CaCl2 and calcium ionophore A 23187, phosphorylation of erythrocyte pyruvate kinase was demonstrated using the double antibody technique and autoradiography. Phosphorylation was inhibited by calmodulin inhibitors, trifluoperazine or ZnCl2. In the presence of purified erythrocyte calmodulin, CaCl2 and [γ-32P] ATP, the partially purified erythrocyte pyruvate kinase containing cytozol protein kinases was phosphorylated. This was also inhibited by trifluoperazine or ZnCl2. From these results, it was concluded that erythrocyte pyruvate kinase is phosphorylated by a calcium-calmodulin dependent process. 相似文献
47.
Nirmala Kotagal Christina Patke Michael Landt Jay McDonald Jerry Colca Paul Lacy Michael McDaniel 《FEBS letters》1982,137(2):249-252
The carboxyl group reagent dicyclohexylcarbodiimide inhibits the electrogenic entry of Cl? and NO3? into rat liver mitochondria at alkaline pH. The inhibition is time dependent and 50% inhibition is obtained by the addition of 3–4 nmol DCCD/mg protein. The blockage of the pH-dependent anion-conducting pore appears to be unrelated to the other known actions of DCCD on rat liver mitochondria but seems similar to its effect on the uncoupling protein of brown adipose tissue. 相似文献
48.
Francisco González-Darós Joaquin Carrasco-Luna Angeles Calatayud Julio Salguero Secundino del Valle-Tascón 《Physiologia plantarum》1993,87(1):68-76
The effect of the 5 calmodulin (CaM) antagonists trifluoperazine (TFP). compound 48/80, N-(6-aminohexyl)-naphthalenesulfonamtde (W-5), N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), and calmidazolium on auxin-dependent medium acidification was investigated in abraded segments of Avena sativa L. cv. Victory I. Buffering capacity, Asn content, and changes in pH of bathing solutions were measured in the presence of these inhibitors. When coleoptiles were treated with TFP or compound 48/80, the Asn content and the buffering capacity increased, thus suggesting that plasma membrane permeability was modified. On the contrary. the effect of calmidazolium, W-5. and W-7 on Asn release and buffering capacity was rather low; only small effects being observable at the highest concentration employed. Calmidazolium and W-7 strongly inhibited auxin-dependent medium acidification. W-5 did not affect medium acidification. The specificity of these CaM antagonists and their effects on medium acidification are discussed. The data adduced is consistent with the working hypothesis which postulates an essential role for the Ca2+ -CaM system on auxin-dependent medium acidification. 相似文献
49.
Peter L. Pingerelli Hiroshi Mizukami Andrew S. Wagner David E. Bartnicki John P. Oliver 《Journal of Protein Chemistry》1990,9(2):169-175
S100a is a heterodimeric, acidic calcium-binding protein that interacts with calmodulin antagonists in a Ca2+-dependent manner. In order to study the behavior of the hydrophobic domain on S100a when bound to Ca2+, its interaction with trifluoperazine (TFP) was investigated using16F nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy. The dissociation constant (K
d) values of TFP, as estimated from the chemical shifts of19F NMR, were 191 and 29 m in the absence and presence of Ca2+, respectively, and were similar to those previously reported for S100b. However, the TFP linewidth in the presence of Ca2+-bound S100a was 65 Hz greater than in the presence of Ca2+-bound S100b. This suggests a slower TFP exchange rate for S100a than for S100b. Thus, the TFP linewidths observed for each isoform may reflect differences in structural and modulatory properties of the Ca2+-dependent hydrophobic domains on S100a and S100b. Additionally, the presence of magnesium had no effect on the observed Ca2+-induced TFP spectral changes in S100a solutions. Circular dichroism studies indicate that Ca2+ induces a small transition from -helix to random coil in S100a; in contrast, the opposite transition is reported for calmodulin (Hennesseyet al., 1987). However, TFP did not significantly alter the secondary structure of Ca2+-bound S100a; this observation is similar to the effect of TFP on Ca2+-bound calmodulin and troponin C (Shimizu and Hatano, 1984; Gariépy and Hodges, 1983). It is, therefore, proposed that TFP binds to a hydrophobic domain on S100a in a fashion similar to other calcium-modulated proteins. 相似文献
50.
The distribution of calmodulin and Ca^2+—activated calmodulin in cell cycle of mouse erythroleukemia cells 总被引:3,自引:0,他引:3
Cell proliferation is accompanied with changing levels of intracellular calmodulin (CaM) and its activation.Prior data from synchronized cell population could not actually stand for various CaM levels in different phases of cell cycle.Here,based upon quantitative measurement of fluorescence in individual cells,a method was developed to investigate intracellular total CaM and Ca^2 -activated CaM contents. Intensity of CaM immunoflurescence gave total CaM level,and Ca^2 -activated CaM was measured by fluorescence intensity of CaM antagonist trifluoperazine (TFP).In mouse erythroleukemia (MEL) cells,total CaM level increased from G1 through S to G2M,reaching a maximum of 2-fold increase,then reduced to half amount after cell division.Meanwhile,Ca^2 -activated CaM also in creased through the cell cycle(G1,S,G2M).Increasing observed in G1 meant that the entry of cells from G1 into S phase may require CaM accumulation,and,equally or even more important,Ca^2 -dependent activation of CaM.Ca^2 -activated CaM decreased after cell division.The results suggested that CaM gene expression and C^2 -modulated CaM activation act synergistically to accomplish the cell cycle progression. 相似文献