Artykuły w czasopismach: „Intramolecular signal transduction”

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Papavassiliou, A. G., M. Treier i D. Bohmann. "Intramolecular signal transduction in c-Jun." EMBO Journal 14, nr 9 (maj 1995): 2014–19. http://dx.doi.org/10.1002/j.1460-2075.1995.tb07193.x.

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Mueller, Sylvia, Claus Liebmann i Siegmund Reissmann. "Intramolecular signal transduction by the bradykinin B2 receptor". International Immunopharmacology 2, nr 13-14 (grudzień 2002): 1763–70. http://dx.doi.org/10.1016/s1567-5769(02)00167-4.

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Lee, Yoonji, Sun Choi i Changbong Hyeon. "Mapping the intramolecular signal transduction of G-protein coupled receptors". Proteins: Structure, Function, and Bioinformatics 82, nr 5 (22.11.2013): 727–43. http://dx.doi.org/10.1002/prot.24451.

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Basith, Shaherin, Balachandran Manavalan, Tae Shin i Gwang Lee. "A Molecular Dynamics Approach to Explore the Intramolecular Signal Transduction of PPAR-α". International Journal of Molecular Sciences 20, nr 7 (3.04.2019): 1666. http://dx.doi.org/10.3390/ijms20071666.

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Dynamics and functions of the peroxisome proliferator-activated receptor (PPAR)-α are modulated by the types of ligands that bind to the orthosteric sites. While several X-ray crystal structures of PPAR-α have been determined in their agonist-bound forms, detailed structural information in their apo and antagonist-bound states are still lacking. To address these limitations, we apply unbiased molecular dynamics simulations to three different PPAR-α systems to determine their modulatory mechanisms. Herein, we performed hydrogen bond and essential dynamics analyses to identify the important residues involved in polar interactions and conformational structural variations, respectively. Furthermore, betweenness centrality network analysis was carried out to identify key residues for intramolecular signaling. The differences observed in the intramolecular signal flow between apo, agonist- and antagonist-bound forms of PPAR-α will be useful for calculating maps of information flow and identifying key residues crucial for signal transductions. The predictions derived from our analysis will be of great help to medicinal chemists in the design of effective PPAR-α modulators and additionally in understanding their regulation and signal transductions.

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Calderwood, S. K., Y. Wang, X. Xie, M. A. Khaleque, S. D. Chou, A. Murshid, T. Prince i Y. Zhang. "Signal Transduction Pathways Leading to Heat Shock Transcription". Signal Transduction Insights 2 (styczeń 2010): STI.S3994. http://dx.doi.org/10.4137/sti.s3994.

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Heat shock proteins (HSP) are essential for intracellular protein folding during stress and protect cells from denaturation and aggregation cascades that can lead to cell death. HSP genes are regulated at the transcriptional level by heat shock transcription factor 1 (HSF1) that is activated by stress and binds to heat shock elements in HSP genes. The activation of HSF1 during heat shock involves conversion from an inert monomer to a DNA binding trimer through a series of intramolecular folding rearrangements. However, the trigger for HSF1 at the molecular level is unclear and hypotheses for this process include reversal of feedback inhibition of HSF1 by molecular chaperones and heat-induced binding to large non-coding RNAs. Heat shock also causes a profound modulation in cell signaling pathways that lead to protein kinase activation and phosphorylation of HSF1 at a number of regulatory serine residues. HSP genes themselves exist in an accessible chromatin conformation already bound to RNA polymerase II. The RNA polymerase II is paused on HSP promoters after transcribing a short RNA sequence proximal to the promoter. Activation by heat shock involves HSF1 binding to the promoter and release of the paused RNA polymerase II followed by further rounds of transcriptional initiation and elongation. HSF1 is thus involved in both initiation and elongation of HSP RNA transcripts. Recent studies indicate important roles for histone modifications on HSP genes during heat shock. Histone modification occurs rapidly after stress and may be involved in promoting nucleosome remodeling on HSP promoters and in the open reading frames of HSP genes. Understanding these processes may be key to evaluating mechanisms of deregulated HSP expression that plays a key role in neurodegeneration and cancer.

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Rohmer, Thierry, Holger Strauss, Jon Hughes, Huub de Groot, Wolfgang Gärtner, Peter Schmieder i Jörg Matysik. "15N MAS NMR Studies of Cph1 Phytochrome: Chromophore Dynamics and Intramolecular Signal Transduction". Journal of Physical Chemistry B 110, nr 41 (październik 2006): 20580–85. http://dx.doi.org/10.1021/jp062454+.

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Weng, Tan-Qing, Yi-Fan Huang, Lou-Sha Xue, Jie Cheng, Shan Jin, Sheng-Hua Liu, De-Yin Wu i George Chen. "Anion-Binding-Induced Electrochemical Signal Transduction in Ferrocenylimidazolium: Combined Electrochemical Experimental and Theoretical Investigation". Molecules 24, nr 2 (10.01.2019): 238. http://dx.doi.org/10.3390/molecules24020238.

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Five ferrocene alkymethylimidazolium cations 1a–1d and 2 with different alkyl spacer lengths were reinvestigated using voltammetry and density functional theory (DFT) calculations. The voltammetric responses of ligand 2 toward various anions are described in detail. An interesting and unprecedented finding from both experimental and theoretical studies is that coupled electron and intramolecular anion (F−) transfer may be present in these molecules. In addition, it was also observed that, in these studied molecules, the electrostatic attraction interaction toward F− would effectively vanish beyond 1 nm, which was previously reported only for cations.

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Neumann, Susanne, Maren Claus i Ralf Paschke. "Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation". European Journal of Endocrinology 152, nr 4 (kwiecień 2005): 625–34. http://dx.doi.org/10.1530/eje.1.01891.

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Objective: The molecular mechanisms of TSH receptor (TSHR) activation and intramolecular signal transduction are largely unknown. Deletion of the extracellular domain (ECD) of the TSHR results in increased constitutive activity, which suggests a self-inhibitory interaction between the ECD and the extracellular loops (ECLs) or the transmembrane domains (TMDs). To investigate these potential interactions and to pursue the idea that mutations in the ECD affect the constitutive activity of mutants in the ECLs or TMDs we generated double mutants between position 281 in the ECD and mutants in all three ECLs as well as the 6th TMD. Design: We combined mutation S281D, characterized by an impaired TSH-stimulated cAMP response, with the constitutively activating in vivo mutations I486F (1st ECL), I568T (2nd ECL), V656F (3rd ECL) and D633F (6th TMD). Further, we constructed double mutants containing the constitutively activating mutation S281N and one of the inactivating mutations D474E, T477I (1st ECL) and D633K (6th TMD). Results: The cAMP level of the double mutants with S281N and the inactive mutants in the 1st ECL was decreased below the level of the inactive single mutants, demonstrating that a constitutively activating mutation in the ECD cannot bypass disruption of signal transduction in the serpentine domain. In double mutants with S281D, basal and TSH-induced cAMP and inositol phosphate production of constitutively active mutants was reduced to the level of S281D. Conclusion: The dominance of S281D and the dependence of constitutively activating mutations in the ECLs on the functionally intact ECD strongly suggest that interactions between these receptor domains are required for TSHR activation and intramolecular signal transduction.

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Röhrig, Ute F., Leonardo Guidoni i Ursula Rothlisberger. "Early Steps of the Intramolecular Signal Transduction in Rhodopsin Explored by Molecular Dynamics Simulations†". Biochemistry 41, nr 35 (wrzesień 2002): 10799–809. http://dx.doi.org/10.1021/bi026011h.

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Basith, Shaherin, Balachandran Manavalan, Tae Hwan Shin i Gwang Lee. "Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics". Biomolecules 11, nr 6 (27.05.2021): 798. http://dx.doi.org/10.3390/biom11060798.

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Glutamate dehydrogenase (GDH) is a ubiquitous enzyme that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate. It acts as an important branch-point enzyme between carbon and nitrogen metabolisms. Due to the multifaceted roles of GDH in cancer, hyperinsulinism/hyperammonemia, and central nervous system development and pathologies, tight control of its activity is necessitated. To date, several GDH structures have been solved in its closed form; however, intrinsic structural information in its open and apo forms are still deficient. Moreover, the allosteric communications and conformational changes taking place in the three different GDH states are not well studied. To mitigate these drawbacks, we applied unbiased molecular dynamic simulations (MD) and network analysis to three different GDH states i.e., apo, active, and inactive forms, for investigating their modulatory mechanisms. In this paper, based on MD and network analysis, crucial residues important for signal transduction, conformational changes, and maps of information flow among the different GDH states were elucidated. Moreover, with the recent findings of allosteric modulators, an allosteric wiring illustration of GDH intramolecular signal transductions would be of paramount importance to obtain the process of this enzyme regulation. The structural insights gained from this study will pave way for large-scale screening of GDH regulators and could support researchers in the design and development of new and potent GDH ligands.

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Ascano, Manuel, i David J. Robbins. "An Intramolecular Association between Two Domains of the Protein Kinase Fused Is Necessary for Hedgehog Signaling". Molecular and Cellular Biology 24, nr 23 (1.12.2004): 10397–405. http://dx.doi.org/10.1128/mcb.24.23.10397-10405.2004.

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ABSTRACT The protein kinase Fused (Fu) is an integral member of the Hedgehog (Hh) signaling pathway. Although genetic studies demonstrate that Fu is required for the regulation of the Hh pathway, the mechanistic role that it plays remains largely unknown. Given our difficulty in developing an in vitro kinase assay for Fu, we reasoned that the catalytic activity of Fu might be highly regulated. Several mechanisms are known to regulate protein kinases, including self-association in either an intra- or an intermolecular fashion. Here, we provide evidence that Hh regulates Fu through intramolecular association between its kinase domain (ΔFu) and its carboxyl-terminal domain (Fu-tail). We show that ΔFu and Fu-tail can interact in trans, with or without the kinesin-related protein Costal 2 (Cos2). However, since the majority of Fu is found associated with Cos2 in vivo, we hypothesized that Fu-tail, which binds Cos2 directly, would be able to tether ΔFu to Cos2. We demonstrate that ΔFu colocalizes with Cos2 in the presence of Fu-tail and that this colocalization occurs on a subset of membrane vesicles previously characterized to be important for Hh signal transduction. Additionally, expression of Fu-tail in fu mutant flies that normally express only the kinase domain rescues the fu wing phenotype. Therefore, reestablishing the association between these two domains of Fu in trans is sufficient to restore Hh signal transduction in vivo. In such a manner we validate our hypothesis, demonstrating that Fu self-associates and is functional in an Hh-dependent manner. Our results here enhance our understanding of one of the least characterized, yet critical, components of Hh signal transduction.

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Vedamalai, Mani, Dhaval Kedaria, Rajesh Vasita, Shigeki Mori i Iti Gupta. "Design and synthesis of BODIPY-clickate based Hg2+ sensors: the effect of triazole binding mode with Hg2+ on signal transduction". Dalton Transactions 45, nr 6 (2016): 2700–2708. http://dx.doi.org/10.1039/c5dt04042f.

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Highly selective BODIPY-clickates for mercury sensing are reported. These BODIPY clickates exhibits emission in red region with unprecedented large Stokes shifts (116 and 154 nm) upon mercury ion binding due to the intramolecular charge transfer processes.

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Hamidi, Sepehr, Chun-Rong Chen, Yumiko Mizutori-Sasai, Sandra M. McLachlan i Basil Rapoport. "Relationship between Thyrotropin Receptor Hinge Region Proteolytic Posttranslational Modification and Receptor Physiological Function". Molecular Endocrinology 25, nr 1 (1.01.2011): 184–94. http://dx.doi.org/10.1210/me.2010-0401.

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The glycoprotein hormone receptor hinge region is the least conserved component and the most variable in size; the TSH receptor (TSHR) being the longest (152 amino acids; residues 261–412). The TSHR is also unique among the glycoprotein hormone receptor in undergoing in vivo intramolecular cleavage into disulfide-linked A- and B-subunits with removal of an intervening ‘C-peptide’ region. Experimentally, hinge region amino acids 317–366 (50 residues) can be deleted without alteration in receptor function. However, in vivo, more than 50 amino acids are deleted during TSHR intramolecular cleavage; furthermore, the boundaries of this deleted region are ragged and poorly defined. Studies to determine the extent to which hinge region deletions can be tolerated without affecting receptor function (‘minimal hinge’) are lacking. Using as a template the functionally normal TSHR with residues 317–366 deleted, progressive downstream extension of deletions revealed residue 371 to be the limit compatible with normal TSH binding and coupling with cAMP signal transduction. Based on the foregoing downstream limit, upstream deletion from residue 307 (307–371 deletion) was also tolerated without functional alteration, as was deletion of residues 303–366. Addressing a related issue regarding the functional role of the TSHR hinge region, we observed that downstream hinge residues 377–384 contribute to coupling ligand binding with cAMP signal transduction. In summary, we report the first evaluation of TSHR function in relation to proteolytic posttranslational hinge region modifications. Deletion of TSHR hinge amino acids 303–366 (64 residues) or 307–371 (65 residues) are the maximum hinge region deletions compatible with normal TSHR function.

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Wang, Mingxing, Qiong Guo, Kongfu Zhu, Bo Fang, Yifan Yang, Maikun Teng, Xu Li i Yuyong Tao. "Interface switch mediates signal transmission in a two-component system". Proceedings of the National Academy of Sciences 117, nr 48 (16.11.2020): 30433–40. http://dx.doi.org/10.1073/pnas.1912080117.

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Two-component systems (TCS), which typically consist of a membrane-embedded histidine kinase and a cytoplasmic response regulator, are the dominant signaling proteins for transduction of environmental stimuli into cellular response pathways in prokaryotic cells. HptRSA is a recently identified TCS consisting of the G6P-associated sensor protein (HptA), transmembrane histidine kinase (HptS), and cytoplasmic effector (HptR). HptRSA mediates glucose-6-phosphate (G6P) uptake to supportStaphylococcus aureusgrowth and multiplication within various host cells. How the mechanism by which HptRSA perceives G6P and triggers a downstream response has remained elusive. Here, we solved the HptA structures in apo and G6P-bound states. G6P binding in the cleft between two HptA domains caused a conformational closing movement. The solved structures of HptA in complex with the periplasmic domain of HptS showed that HptA interacts with HptS through both constitutive and switchable interfaces. The G6P-free form of HptA binds to the membrane-distal side of the HptS periplasmic domain (HptSp), resulting in a parallel conformation of the HptSp protomer pair. However, once HptA associates with G6P, its intramolecular domain closure switches the HptA-HptSp contact region into the membrane-proximal domain, which causes rotation and closure of the C termini of each HptSp protomer. Through biochemical and growth assays of HptA and HptS mutant variants, we proposed a distinct mechanism of interface switch-mediated signaling transduction. Our results provide mechanistic insights into bacterial nutrient sensing and expand our understanding of the activation modes by which TCS communicates external signals.

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Ma, Cheng-Wei, Zhi-Long Xiu i An-Ping Zeng. "Discovery of Intramolecular Signal Transduction Network Based on a New Protein Dynamics Model of Energy Dissipation". PLoS ONE 7, nr 2 (20.02.2012): e31529. http://dx.doi.org/10.1371/journal.pone.0031529.

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Jaggi, R. "The two opposing activities of adenylyl transferase reside in distinct homologous domains, with intramolecular signal transduction". EMBO Journal 16, nr 18 (15.09.1997): 5562–71. http://dx.doi.org/10.1093/emboj/16.18.5562.

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Hanique, Sophie, Maria-Luigi Colombo, Erik Goormaghtigh, Patrice Soumillion, Jean-Marie Frère i Bernard Joris. "Evidence of an Intramolecular Interaction between the Two Domains of the BlaR1 Penicillin Receptor during the Signal Transduction". Journal of Biological Chemistry 279, nr 14 (21.01.2004): 14264–72. http://dx.doi.org/10.1074/jbc.m313488200.

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Re, Sandra Da, Stéphane Bertagnoli, Joëlle Fourment, Jean-Marc Reyrat i Daniel Kahn. "Intramolecular signal transduction within the FixJ transcriptional activator:in vitroevidence for the inhibitory effect of the phosphorylatable regulatory domain". Nucleic Acids Research 22, nr 9 (1994): 1555–61. http://dx.doi.org/10.1093/nar/22.9.1555.

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Schulam, P. G., i W. T. Shearer. "Evidence for 5-lipoxygenase activity in human B cell lines. A possible role for arachidonic acid metabolites during B cell signal transduction." Journal of Immunology 144, nr 7 (1.04.1990): 2696–701. http://dx.doi.org/10.4049/jimmunol.144.7.2696.

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Abstract Ligand binding to B lymphocytes via membrane Ig initiates a cascade of events beginning with the hydrolysis of phosphatidylinositol 4,5-bisphosphate into diacylglycerol and inositol 1,4,5-trisphosphate. Subsequent to the activation of protein kinase C and the induction of a rise in intracellular calcium by diacylglycerol and inositol 1,4,5-trisphosphate, there is gene transcription and eventually cellular activation. By mimicking the initial event of B cell activation with phorbol ester and calcium ionophore one can begin to identify the many mediators used in signaling between the membrane and the nucleus. We have examined the effect of calcium on arachidonic acid (AA) metabolism in several EBV-transformed human B cell lines. The cells were labelled with [3H]AA and stimulated with the calcium ionophore A23187. Analysis of the supernatant by reversed-phase HPLC demonstrated a dose-dependent release of an AA metabolite that coeluted with authentic 5-hydroxyeicosatetraenoic acid (5-HETE). In addition, the AA metabolite coeluted with standard 5-HETE under straight-phase chromatography. Further analysis by RIA confirmed the identification of 5-HETE and revealed an additional metabolite, 5-HETE lactone (5-HL). 5-HL is the intramolecular ester of 5-HETE generated in the presence of acid. We were unable to convert [3H] 5-HETE into 5-HL during sample preparation unless cells were present, suggesting that the 5-HL, is of cellular origin. These results suggest that the AA metabolites 5-HETE and its intramolecular ester 5-HL may play a role in B cell activation because they are produced subsequent to a rise in intracellular Ca2+, an event that occurs during cross-linking of membrane Ig.

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Yamashita, Takahiro, Masataka Yanagawa i Yoshinori Shichida. "2P342 Intramolecular signal transduction through helices II and IV of metabotropic glutamate receptor(Photobiology-vision and photoreception,Oral Presentations)". Seibutsu Butsuri 47, supplement (2007): S198. http://dx.doi.org/10.2142/biophys.47.s198_3.

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Elliott, Kathryn T., Igor B. Zhulin, Jeanne A. Stuckey i Victor J. DiRita. "Conserved Residues in the HAMP Domain Define a New Family of Proposed Bipartite Energy Taxis Receptors". Journal of Bacteriology 191, nr 1 (24.10.2008): 375–87. http://dx.doi.org/10.1128/jb.00578-08.

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ABSTRACT HAMP domains, found in many bacterial signal transduction proteins, generally transmit an intramolecular signal between an extracellular sensory domain and an intracellular signaling domain. Studies of HAMP domains in proteins where both the input and output signals occur intracellularly are limited to those of the Aer energy taxis receptor of Escherichia coli, which has both a HAMP domain and a sensory PAS domain. Campylobacter jejuni has an energy taxis system consisting of the domains of Aer divided between two proteins, CetA (HAMP domain containing) and CetB (PAS domain containing). In this study, we found that the CetA HAMP domain differs significantly from that of Aer in the predicted secondary structure. Using similarity searches, we identified 55 pairs of HAMP/PAS proteins encoded by adjacent genes in a diverse group of microorganisms. We propose that these HAMP/PAS pairs form a new family of bipartite energy taxis receptors. Within these proteins, we identified nine residues in the HAMP domain and proximal signaling domain that are highly conserved, at least three of which are required for CetA function. Additionally, we demonstrated that CetA contributes to the invasion of human epithelial cells by C. jejuni, while CetB does not. This finding supports the hypothesis that members of HAMP/PAS pairs possess the capacity to act independently of each other in cellular traits other than energy taxis.

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WANG, Zhi-Xin, i Jia-Wei WU. "Autophosphorylation kinetics of protein kinases". Biochemical Journal 368, nr 3 (15.12.2002): 947–52. http://dx.doi.org/10.1042/bj20020557.

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Protein kinases play a central role in cellular signal transduction, by transmitting biochemical information between activated membrane-bound receptors and physiological target proteins. In addition to phosphorylating other proteins, almost all protein kinases catalyse autophosphorylation reactions (i.e. reactions in which the kinase serves as its own substrate). The autophosphorylation reactions can be intramolecular or intermolecular. In the present study, a detailed kinetic analysis of the intermolecular autophosphorylation reaction is presented. On the basis of the kinetic equations, a new procedure is developed to evaluate the kinetic parameters of the autophosphorylation reaction. This method was used to analyse the intermolecular autophosphorylation of an S6/H4 kinase from human placenta. At a fixed ATP concentration of 0.125mM, the apparent catalytic-centre activity (turnover number; kcat) and apparent Michaelis—Menten constant (Km) for the autophosphorylation reaction were determined to be 0.91min-1 and 0.86μM respectively.

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Lang, Michael J., Bethany S. Strunk, Nadia Azad, Jason L. Petersen i Lois S. Weisman. "An intramolecular interaction within the lipid kinase Fab1 regulates cellular phosphatidylinositol 3,5-bisphosphate lipid levels". Molecular Biology of the Cell 28, nr 7 (kwiecień 2017): 858–64. http://dx.doi.org/10.1091/mbc.e16-06-0390.

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Phosphorylated phosphoinositide lipids (PPIs) are low-abundance signaling molecules that control signal transduction pathways and are necessary for cellular homeostasis. The PPI phosphatidylinositol (3,5)-bisphosphate (PI(3,5)P2) is essential in multiple organ systems. PI(3,5)P2 is generated from PI3P by the conserved lipid kinase Fab1/PIKfyve. Defects in the dynamic regulation of PI(3,5)P2 are linked to human diseases. However, few mechanisms that regulate PI(3,5)P2 have been identified. Here we report an intramolecular interaction between the yeast Fab1 kinase region and an upstream conserved cysteine-rich (CCR) domain. We identify mutations in the kinase domain that lead to elevated levels of PI(3,5)P2 and impair the interaction between the kinase and CCR domain. We also identify mutations in the CCR domain that lead to elevated levels of PI(3,5)P2. Together these findings reveal a regulatory mechanism that involves the CCR domain of Fab1 and contributes to dynamic control of cellular PI(3,5)P2 synthesis.

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Kazemein Jasemi, Neda S., Christian Herrmann, Eva Magdalena Estirado, Lothar Gremer, Dieter Willbold, Luc Brunsveld, Radovan Dvorsky i Mohammad R. Ahmadian. "The intramolecular allostery of GRB2 governing its interaction with SOS1 is modulated by phosphotyrosine ligands". Biochemical Journal 478, nr 14 (23.07.2021): 2793–809. http://dx.doi.org/10.1042/bcj20210105.

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Growth factor receptor-bound protein 2 (GRB2) is a trivalent adaptor protein and a key element in signal transduction. It interacts via its flanking nSH3 and cSH3 domains with the proline-rich domain (PRD) of the RAS activator SOS1 and via its central SH2 domain with phosphorylated tyrosine residues of receptor tyrosine kinases (RTKs; e.g. HER2). The elucidation of structural organization and mechanistic insights into GRB2 interactions, however, remain challenging due to their inherent ﬂexibility. This study represents an important advance in our mechanistic understanding of how GRB2 links RTKs to SOS1. Accordingly, it can be proposed that (1) HER2 pYP-bound SH2 potentiates GRB2 SH3 domain interactions with SOS1 (an allosteric mechanism); (2) the SH2 domain blocks cSH3, enabling nSH3 to bind SOS1 first before cSH3 follows (an avidity-based mechanism); and (3) the allosteric behavior of cSH3 to other domains appears to be unidirectional, although there is an allosteric effect between the SH2 and SH3 domains.

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Oishi, Koichiro, Mayu Nagamori, Yasuhiro Kashino, Hiroshi Sekiguchi, Yuji C. Sasaki, Atsuo Miyazawa i Yuri Nishino. "Ligand-Dependent Intramolecular Motion of Native Nicotinic Acetylcholine Receptors Determined in Living Myotube Cells via Diffracted X-ray Tracking". International Journal of Molecular Sciences 24, nr 15 (28.07.2023): 12069. http://dx.doi.org/10.3390/ijms241512069.

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Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that play an important role in signal transduction at the neuromuscular junction (NMJ). Movement of the nAChR extracellular domain following agonist binding induces conformational changes in the extracellular domain, which in turn affects the transmembrane domain and opens the ion channel. It is known that the surrounding environment, such as the presence of specific lipids and proteins, affects nAChR function. Diffracted X-ray tracking (DXT) facilitates measurement of the intermolecular motions of receptors on the cell membranes of living cells, including all the components involved in receptor function. In this study, the intramolecular motion of the extracellular domain of native nAChR proteins in living myotube cells was analyzed using DXT for the first time. We revealed that the motion of the extracellular domain in the presence of an agonist (e.g., carbamylcholine, CCh) was restricted by an antagonist (i.e., alpha-bungarotoxin, BGT).

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Sasidharan, Santanu, Kamalakannan Radhakrishnan, Jun-Yeong Lee, Prakash Saudagar, Vijayakumar Gosu i Donghyun Shin. "Molecular dynamics of the ERRγ ligand-binding domain bound with agonist and inverse agonist". PLOS ONE 18, nr 4 (6.04.2023): e0283364. http://dx.doi.org/10.1371/journal.pone.0283364.

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Estrogen-related receptor gamma (ERRγ), the latest member of the ERR family, does not have any known reported natural ligands. Although the crystal structures of the apo, agonist-bound, and inverse agonist-bound ligand-binding domain (LBD) of ERRγ have been solved previously, their dynamic behavior has not been studied. Hence, to explore the intrinsic dynamics of the apo and ligand-bound forms of ERRγ, we applied long-range molecular dynamics (MD) simulations to the crystal structures of the apo and ligand-bound forms of the LBD of ERRγ. Using the MD trajectories, we performed hydrogen bond and binding free energy analysis, which suggested that the agonist displayed more hydrogen bonds with ERRγ than the inverse agonist 4-OHT. However, the binding energy of 4-OHT was higher than that of the agonist GSK4716, indicating that hydrophobic interactions are crucial for the binding of the inverse agonist. From principal component analysis, we observed that the AF-2 helix conformation at the C-terminal domain was similar to the initial structures during simulations, indicating that the AF-2 helix conformation is crucial with respect to the agonist or inverse agonist for further functional activity of ERRγ. In addition, we performed residue network analysis to understand intramolecular signal transduction within the protein. The betweenness centrality suggested that few of the amino acids are important for residue signal transduction in apo and ligand-bound forms. The results from this study may assist in designing better therapeutic compounds against ERRγ associated diseases.

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Ji, Inhae, ChangWoo Lee, YongSang Song, P. Michael Conn i Tae H. Ji. "Cis- and Trans-Activation of Hormone Receptors: the LH Receptor". Molecular Endocrinology 16, nr 6 (1.06.2002): 1299–308. http://dx.doi.org/10.1210/mend.16.6.0852.

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Abstract G protein-coupled receptors (GPCRs) accommodate a wide spectrum of activators from ions to glycoprotein hormones. The mechanism of activation for this large and clinically important family of receptors is poorly understood. Although initially thought to function as monomers, there is a growing body of evidence that GPCR dimers form, and in some cases that these dimers are essential for signal transduction. Here we describe a novel mechanism of intermolecular GPCR activation, which we refer to as trans-activation, in the LH receptor, a GPCR that does not form stable dimers. The LH receptor consists of a 350-amino acid amino-terminal domain, which is responsible for high-affinity binding to human CG, followed by seven-transmembrane domains and connecting loops. This seven-transmembrane domain bundle transmits the signal from the extracellular amino terminus to intracellular G proteins and adenylyl cyclase. Here, we show that binding of hormone to one receptor can activate adenylyl cyclase through its transmembrane bundle, intramolecular activation (cis-activation), as well as trans-activation through the transmembrane bundle of an adjacent receptor, without forming a stable receptor dimer. Coexpression of a mutant receptor defective in hormone binding and another mutant defective in signal generation rescues hormone-activated cAMP production. Our observations provide new insights into the mechanism of receptor activation mechanisms and have implications for the treatment of inherited disorders of glycoprotein hormone receptors.

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Hu, Zhongjun, Dianne W. Taylor, Michael K. Reedy, Robert J. Edwards i Kenneth A. Taylor. "Structure of myosin filaments from relaxed Lethocerus flight muscle by cryo-EM at 6 Å resolution". Science Advances 2, nr 9 (wrzesień 2016): e1600058. http://dx.doi.org/10.1126/sciadv.1600058.

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We describe a cryo–electron microscopy three-dimensional image reconstruction of relaxed myosin II–containing thick filaments from the flight muscle of the giant water bug Lethocerus indicus. The relaxed thick filament structure is a key element of muscle physiology because it facilitates the reextension process following contraction. Conversely, the myosin heads must disrupt their relaxed arrangement to drive contraction. Previous models predicted that Lethocerus myosin was unique in having an intermolecular head-head interaction, as opposed to the intramolecular head-head interaction observed in all other species. In contrast to the predicted model, we find an intramolecular head-head interaction, which is similar to that of other thick filaments but oriented in a distinctly different way. The arrangement of myosin’s long α-helical coiled-coil rod domain has been hypothesized as either curved layers or helical subfilaments. Our reconstruction is the first report having sufficient resolution to track the rod α helices in their native environment at resolutions ~5.5 Å, and it shows that the layer arrangement is correct for Lethocerus. Threading separate paths through the forest of myosin coiled coils are four nonmyosin peptides. We suggest that the unusual position of the heads and the rod arrangement separated by nonmyosin peptides are adaptations for mechanical signal transduction whereby applied tension disrupts the myosin heads as a component of stretch activation.

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Zhurinsky, J., M. Shtutman i A. Ben-Ze'ev. "Plakoglobin and beta-catenin: protein interactions, regulation and biological roles". Journal of Cell Science 113, nr 18 (15.09.2000): 3127–39. http://dx.doi.org/10.1242/jcs.113.18.3127.

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Beta-catenin can play different roles in the cell, including one as a structural protein at cell-cell adherens junctions and another as a transcriptional activator mediating Wnt signal transduction. Plakoglobin (gamma)-catenin), a close homolog of beta-catenin, shares with beta-catenin common protein partners and can fulfill some of the same functions. The complexing of catenins with various protein partners is regulated by phosphorylation and by intramolecular interactions. The competition between different catenin partners for binding to catenins mediates the cross-talk between cadherin-based adhesion, catenin-dependent transcription and Wnt signaling. Although plakoglobin differs from beta-catenin in its functions and is unable to compensate for defects in Wnt signaling resulting from lack of beta-catenin, recent evidence suggests that plakoglobin plays a unique role in Wnt signaling that is different from that of beta-catenin. The functional difference between catenins is reflected in their differential involvement in embryonic development and cancer progression.

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30

Sadeghi, Maryam, Jens Balke, Timm Rafaluk-Mohr i Ulrike Alexiev. "Long-Distance Protonation-Conformation Coupling in Phytochrome Species". Molecules 27, nr 23 (1.12.2022): 8395. http://dx.doi.org/10.3390/molecules27238395.

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Phytochromes are biological red/far-red light sensors found in many organisms. The connection between photoconversion and the cellular output signal involves light-mediated global structural changes in the interaction between the photosensory module (PAS-GAF-PHY, PGP) and the C-terminal transmitter (output) module. We recently showed a direct correlation of chromophore deprotonation with pH-dependent conformational changes in the various domains of the prototypical phytochrome Cph1 PGP. These results suggested that the transient phycocyanobilin (PCB) chromophore deprotonation is closely associated with a higher protein mobility both in proximal and distal protein sites, implying a causal relationship that might be important for the global large-scale protein rearrangements. Here, we investigate the prototypical biliverdin (BV)-binding phytochrome Agp1. The structural changes at various positions in Agp1 PGP were investigated as a function of pH using picosecond time-resolved fluorescence anisotropy and site-directed fluorescence labeling of cysteine variants of Agp1 PGP. We show that the direct correlation of chromophore deprotonation with pH-dependent conformational changes does not occur in Agp1. Together with the absence of long-range effects between the PHY domain and chromophore pKa, in contrast to the findings in Cph1, our results imply phytochrome species-specific correlations between transient chromophore deprotonation and intramolecular signal transduction.

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Resh, Marilyn D. "Open Biology: overview for special issue on dynamics of protein fatty acylation". Open Biology 11, nr 9 (wrzesień 2021): 210228. http://dx.doi.org/10.1098/rsob.210228.

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Fatty acylation is a widespread form of protein modification that occurs on specific intracellular and secreted proteins. Beyond increasing hydrophobicity and the affinity of the modified protein for lipid bilayers, covalent attachment of a fatty acid exerts effects on protein localization, inter- and intramolecular interactions and signal transduction. As such, research into protein fatty acylation has been embraced by an extensive community of biologists. This special issue highlights advances at the forefront of the field, by focusing on two families of enzymes that catalyse post-translational protein fatty acylation, zDHHC palmitoyl acyltransferases and membrane-bound O-acyl transferases, and signalling pathways regulated by their fatty acylated protein substrates. The collected contributions catalogue the tremendous progress that has been made in enzyme and substrate identification. In addition, articles in this special issue provide insights into the pivotal functions of fatty acylated proteins in immune cell, insulin and EGF receptor-mediated signalling pathways. As selective inhibitors of protein fatty acyltransferases are generated, the future holds great promise for therapeutic targeting of fatty acyltransferases that play key roles in human disease.

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Nichols, James T., Alison Miyamoto, Samantha L. Olsen, Brendan D'Souza, Christine Yao i Gerry Weinmaster. "DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur". Journal of Cell Biology 176, nr 4 (12.02.2007): 445–58. http://dx.doi.org/10.1083/jcb.200609014.

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Cleavage of Notch by furin is required to generate a mature, cell surface heterodimeric receptor that can be proteolytically activated to release its intracellular domain, which functions in signal transduction. Current models propose that ligand binding to heterodimeric Notch (hNotch) induces a disintegrin and metalloprotease (ADAM) proteolytic release of the Notch extracellular domain (NECD), which is subsequently shed and/or endocytosed by DSL ligand cells. We provide evidence for NECD release and internalization by DSL ligand cells, which, surprisingly, did not require ADAM activity. However, losses in either hNotch formation or ligand endocytosis significantly decreased NECD transfer to DSL ligand cells, as well as signaling in Notch cells. Because endocytosis-defective ligands bind hNotch, but do not dissociate it, additional forces beyond those produced through ligand binding must function to disrupt the intramolecular interactions that keep hNotch intact and inactive. Based on our findings, we propose that mechanical forces generated during DSL ligand endocytosis function to physically dissociate hNotch, and that dissociation is a necessary step in Notch activation.

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Nagy, Szilvia K., Zsuzsanna Darula, Brigitta M. Kállai, László Bögre, Gábor Bánhegyi, Katalin F. Medzihradszky, Gábor V. Horváth i Tamás Mészáros. "Activation of AtMPK9 through autophosphorylation that makes it independent of the canonical MAPK cascades". Biochemical Journal 467, nr 1 (20.03.2015): 167–75. http://dx.doi.org/10.1042/bj20141176.

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Mitogen-activated protein kinases (MAPKs) are part of conserved signal transduction modules in eukaryotes that are typically organized into three-tiered kinase cascades. The activation of MAPKs in these pathways is fully dependent on the bisphosphorylation of the TXY motif in the T-loop by the pertinent dual-specificity MAPK kinases (MAPKKs). The Arabidopsis mitogen-activated protein kinase 9 (AtMPK9) is a member of an atypical class of MAPKs. Representatives of this MAPK family have a TDY phosphoacceptor site, a long C-terminal extension and lack the common MAPKK-binding docking motif. In the present paper, we describe multiple in vitro and in vivo data showing that AtMPK9 is activated independently of any upstream MAPKKs but rather is activated through autophosphorylation. We mapped the autophosphorylation sites by MS to the TDY motif and to the C-terminal regulatory extension. We mutated the phosphoacceptor sites on the TDY, which confirmed the requirement for bisphorylation at this site for full kinase activity. Next, we demonstrated that the kinase-inactive mutant form of AtMPK9 is not trans-phosphorylated on the TDY site when mixed with an active AtMPK9, implying that the mechanism of the autocatalytic phosphorylation is intramolecular. Furthermore, we show that in vivo AtMPK9 is activated by salt and is regulated by okadaic acid-sensitive phosphatases. We conclude that the plant AtMPK9 shows similarities to the mammalian atypical MAPKs, such as extracellular-signal-regulated kinase (ERK) 7/8, in terms of an MAPKK-independent activation mechanism.

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Stamperna, Konstantina, Themistoklis Giannoulis, Eleni Dovolou, Maria Kalemkeridou, Ioannis Nanas, Katerina Dadouli, Katerina Moutou, Zissis Mamuris i Georgios S. Amiridis. "Heat Shock Protein 70 Improves In Vitro Embryo Yield and Quality from Heat Stressed Bovine Oocytes". Animals 11, nr 6 (16.06.2021): 1794. http://dx.doi.org/10.3390/ani11061794.

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Heat shock protein 70 (HSP70) is a chaperon that stabilizes unfolded or partially folded proteins, preventing inappropriate inter- and intramolecular interactions. Here, we examined the developmental competence of in vitro matured oocytes exposed to heat stress with or without HSP70. Bovine oocytes were matured for 24 h at 39 °C without (group C39) or with HSP70 (group H39) and at 41 °C for the first 6 h, followed by 16 h at 39 °C with (group H41) or without HSP70 (group C41). After insemination, zygotes were cultured for 9 days at 39 °C. Cleavage and embryo yield were assessed 48 h post insemination and on days 7, 8, 9, respectively. Gene expression was assessed by RT-PCR in oocytes, cumulus cells and blastocysts. In C41, blastocysts formation rate was lower than in C39 and on day 9 it was lower than in H41. In oocytes, HSP70 enhanced the expression of three HSP genes regardless of incubation temperature. HSP70 at 39 °C led to tight coordination of gene expression in oocytes and blastocysts, but not in cumulus cells. Our results imply that HSP70, by preventing apoptosis, supporting signal transduction, and increasing antioxidant protection of the embryo, protects heat stressed maturing bovine oocyte and restores its developmental competence.

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35

Toutant, Madeleine, Alicia Costa, Jeanne-Marie Studler, Gress Kadaré, Michèle Carnaud i Jean-Antoine Girault. "Alternative Splicing Controls the Mechanisms of FAK Autophosphorylation". Molecular and Cellular Biology 22, nr 22 (15.11.2002): 7731–43. http://dx.doi.org/10.1128/mcb.22.22.7731-7743.2002.

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ABSTRACT Focal adhesion kinase (FAK) is activated following integrin engagement or stimulation of transmembrane receptors. Autophosphorylation of FAK on Tyr-397 is a critical event, allowing binding of Src family kinases and activation of signal transduction pathways. Tissue-specific alternative splicing generates several isoforms of FAK with different autophosphorylation rates. Despite its importance, the mechanisms of FAK autophosphorylation and the basis for differences between isoforms are not known. We addressed these questions using isoforms of FAK expressed in brain. Autophosphorylation of FAK+, which is identical to that of “standard” FAK, was intermolecular in transfected cells, although it did not involve the formation of stable multimeric complexes. Coumermycin-induced dimerization of gyrase B-FAK+ chimeras triggered autophosphorylation of Tyr-397. This was independent of cell adhesion but required the C terminus of the protein. In contrast, the elevated autophosphorylation of FAK+6,7, the major neuronal splice isoform, was not accounted for by transphosphorylation. Specifically designed immune precipitate kinase assays confirmed that autophosphorylation of FAK+ was intermolecular, whereas autophosphorylation of FAK+6,7 or FAK+7 was predominantly intramolecular and insensitive to the inhibitory effects of the N-terminal domain. Our results clarify the mechanisms of FAK activation and show how alternative splicing can dramatically alter the mechanism of autophosphorylation of a protein kinase.

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Chin, Arnold I.-Dah, Junyan Shu, Chong Shan Shi, Zhengbin Yao, John H. Kehrl i Genhong Cheng. "TANK Potentiates Tumor Necrosis Factor Receptor-Associated Factor-Mediated c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase Activation through the Germinal Center Kinase Pathway". Molecular and Cellular Biology 19, nr 10 (1.10.1999): 6665–72. http://dx.doi.org/10.1128/mcb.19.10.6665.

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ABSTRACT Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are mediators of many members of the TNF receptor superfamily and can activate both the nuclear factor κB (NF-κB) and stress-activated protein kinase (SAPK; also known as c-Jun N-terminal kinase) signal transduction pathways. We previously described the involvement of a TRAF-interacting molecule, TRAF-associated NF-κB activator (TANK), in TRAF2-mediated NF-κB activation. Here we show that TANK synergized with TRAF2, TRAF5, and TRAF6 but not with TRAF3 in SAPK activation. TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR). However, when coexpressed, they formed a strong complex with GCKR, thereby providing a potential mechanism for TRAF and TANK synergy in GCKR-mediated SAPK activation, which is important in TNF family receptor signaling. Our results also suggest that TANK can form potential intermolecular as well as intramolecular interactions between its amino terminus and carboxyl terminus. This study suggests that TANK is a regulatory molecule controlling the threshold of NF-κB and SAPK activities in response to activation of TNF receptors. In addition, CD40 activated endogenous GCKR in primary B cells, implicating GCK family proteins in CD40-mediated B-cell functions.

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37

Pasquale, E. B. "Identification of chicken embryo kinase 5, a developmentally regulated receptor-type tyrosine kinase of the Eph family." Cell Regulation 2, nr 7 (lipiec 1991): 523–34. http://dx.doi.org/10.1091/mbc.2.7.523.

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Chicken embryo kinase 5 (Cek5) is a transmembrane tyrosine kinase of the Eph family that was identified by screening a 10-d chicken embryo cDNA expression library with anti-phosphotyrosine antibodies. The extracellular region of Cek5 contains a cysteine rich N-terminal subdomain and a C-terminal subdomain mostly devoid of cysteines and comprising two repeats similar to fibronectin type III repeats. Immunoblotting experiments with anti-Cek5 polyclonal antibodies indicated that Cek5 is a membrane-associated 120-kDa protein containing intramolecular (but not intermolecular) disulfide bonds. Cek5 is already expressed in 2-d-old chicken embryos and is also expressed, at higher levels, later in development. In 10-d-old chicken embryos, Cek5 is expressed at substantial levels in nearly all the tissues examined, whereas in adult it is expressed predominantly in the brain. The expression of Cek5 in the brain gradually diminishes during embryonic development, whereas in the skeletal muscle of the thigh a sharp decrease in Cek5 expression was detected at the time of terminal muscle differentiation. Its wide tissue distribution throughout development and its sustained expression in adult brain suggest that Cek5 is an important component of signal transduction pathways, likely to interact with a widely distributed and important ligand, which is as yet unknown.

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38

Gottardi, Cara J., i Barry M. Gumbiner. "Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes". Journal of Cell Biology 167, nr 2 (18.10.2004): 339–49. http://dx.doi.org/10.1083/jcb.200402153.

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β-Catenin plays essential roles in both cell–cell adhesion and Wnt signal transduction, but what precisely controls β-catenin targeting to cadherin adhesive complexes, or T-cell factor (TCF)-transcriptional complexes is less well understood. We show that during Wnt signaling, a form of β-catenin is generated that binds TCF but not the cadherin cytoplasmic domain. The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of β-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism. Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation. In contrast, the main cadherin-binding form of β-catenin is a β-catenin–α-catenin dimer, indicating that there is a distinct molecular form of β-catenin that can interact with both the cadherin and α-catenin. We propose that participation of β-catenin in adhesion or Wnt signaling is dictated by the regulation of distinct molecular forms of β-catenin with different binding properties, rather than simple competition between cadherins and TCFs for a single constitutive form. This model explains how cells can control whether β-catenin is used independently in cell adhesion and nuclear signaling, or competitively so that the two processes are coordinated and interrelated.

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39

Adolph, Dörte, Nadine Flach, Katharina Mueller, Dirk H. Ostareck i Antje Ostareck-Lederer. "Deciphering the Cross Talk between hnRNP K and c-Src: the c-Src Activation Domain in hnRNP K Is Distinct from a Second Interaction Site". Molecular and Cellular Biology 27, nr 5 (18.12.2006): 1758–70. http://dx.doi.org/10.1128/mcb.02014-06.

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ABSTRACT The protein tyrosine kinase c-Src is regulated by two intramolecular interactions. The repressed state is achieved through the interaction of the Src homology 2 (SH2) domain with the phosphorylated C-terminal tail and the association of the SH3 domain with a polyproline type II helix formed by the linker region between SH2 and the kinase domain. hnRNP K, the founding member of the KH domain protein family, is involved in chromatin remodeling, regulation of transcription, and translation of specific mRNAs and is a target in different signal transduction pathways. In particular, it functions as a specific activator and a substrate of the tyrosine kinase c-Src. Here we address the question how hnRNP K interacts with and activates c-Src. We define the proline residues in hnRNP K in the proline-rich motifs P2 (amino acids [aa] 285 to 297) and P3 (aa 303 to 318), which are necessary and sufficient for the specific activation of c-Src, and we dissect the amino acid sequence (aa 216 to 226) of hnRNP K that mediates a second interaction with c-Src. Our findings indicate that the interaction with c-Src and the activation of the kinase are separable functions of hnRNP K. hnRNP K acts as a scaffold protein that integrates signaling cascades by facilitating the cross talk between kinases and factors that mediate nucleic acid-directed processes.

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Lehtonen, Siri T., Piia M. H. Markkanen, Mirva Peltoniemi, Sang Won Kang i Vuokko L. Kinnula. "Variable overoxidation of peroxiredoxins in human lung cells in severe oxidative stress". American Journal of Physiology-Lung Cellular and Molecular Physiology 288, nr 5 (maj 2005): L997—L1001. http://dx.doi.org/10.1152/ajplung.00432.2004.

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Peroxiredoxins (Prxs) are a group of thiol containing proteins that participate both in signal transduction and in the breakdown of hydrogen peroxide (H2O2) during oxidative stress. Six distinct Prxs have been characterized in human cells (Prxs I–VI). Prxs I–IV form dimers held together by disulfide bonds, Prx V forms intramolecular bond, but the mechanism of Prx VI, so-called 1-Cys Prx, is still unclear. Here we describe the regulation of all six Prxs in cultured human lung A549 and BEAS-2B cells. The cells were exposed to variable concentrations of H2O2, menadione, tumor necrosis factor-α or transforming growth factor-β. To evoke glutathione depletion, the cells were furthermore treated with buthionine sulfoximine. Only high concentrations (300 μM) of H2O2 caused a minor increase (<28%, 4 h) in the expression of Prxs I, IV, and VI. Severe oxidant stress (250–500 μM H2O2) caused a significant increase in the proportion of the monomeric forms of Prxs I–IV; this was reversible at lower H2O2 concentrations (≤250 μM). This recovery of Prx overoxidation differed among the various Prxs; Prx I was recovered within 24 h, but recovery required 48 h for Prx III. Overall, Prxs are not significantly modulated by mild oxidant stress or cytokines, but there is variable, though reversible, overoxidation in these proteins during severe oxidant exposure.

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Dumont, Mark E., i James B. Konopka. "Comparison of Experimental Approaches Used to Determine the Structure and Function of the Class D G Protein-Coupled Yeast α-Factor Receptor". Biomolecules 12, nr 6 (30.05.2022): 761. http://dx.doi.org/10.3390/biom12060761.

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The Saccharomyces cerevisiae α-factor mating pheromone receptor (Ste2p) has been studied as a model for the large medically important family of G protein-coupled receptors. Diverse yeast genetic screens and high-throughput mutagenesis of STE2 identified a large number of loss-of-function, constitutively-active, dominant-negative, and intragenic second-site suppressor mutants as well as mutations that specifically affect pheromone binding. Facile genetic manipulation of Ste2p also aided in targeted biochemical approaches, such as probing the aqueous accessibility of substituted cysteine residues in order to identify the boundaries of the seven transmembrane segments, and the use of cysteine disulfide crosslinking to identify sites of intramolecular contacts in the transmembrane helix bundle of Ste2p and sites of contacts between the monomers in a Ste2p dimer. Recent publication of a series of high-resolution cryo-EM structures of Ste2p in ligand-free, agonist-bound and antagonist-bound states now makes it possible to evaluate the results of these genetic and biochemical strategies, in comparison to three-dimensional structures showing activation-related conformational changes. The results indicate that the genetic and biochemical strategies were generally effective, and provide guidance as to how best to apply these experimental strategies to other proteins. These strategies continue to be useful in defining mechanisms of signal transduction in the context of the available structures and suggest aspects of receptor function beyond what can be discerned from the available structures.

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Williams, Danielle M., David C. Thorn, Christopher M. Dobson, Sarah Meehan, Sophie E. Jackson, Joanna M. Woodcock i John A. Carver. "The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ". Molecules 26, nr 20 (11.10.2021): 6120. http://dx.doi.org/10.3390/molecules26206120.

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14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer’s and Parkinson’s diseases, respectively, a process that is intimately linked to the diseases’ progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ40) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of 15N-labeled Aβ40 and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ40 (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ40 and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.

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43

Martín-Moldes, Zaira, Blas Blázquez, Claudine Baraquet, Caroline S. Harwood, María T. Zamarro i Eduardo Díaz. "Degradation of cyclic diguanosine monophosphate by a hybrid two-component protein protects Azoarcus sp. strain CIB from toluene toxicity". Proceedings of the National Academy of Sciences 113, nr 46 (31.10.2016): 13174–79. http://dx.doi.org/10.1073/pnas.1615981113.

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Cyclic diguanosine monophosphate (c-di-GMP) is a second messenger that controls diverse functions in bacteria, including transitions from planktonic to biofilm lifestyles, virulence, motility, and cell cycle. Here we describe TolR, a hybrid two-component system (HTCS), from the β-proteobacterium Azoarcus sp. strain CIB that degrades c-di-GMP in response to aromatic hydrocarbons, including toluene. This response protects cells from toluene toxicity during anaerobic growth. Whereas wild-type cells tolerated a sudden exposure to a toxic concentration of toluene, a tolR mutant strain or a strain overexpressing a diguanylate cyclase gene lost viability upon toluene shock. TolR comprises an N-terminal aromatic hydrocarbon-sensing Per–Arnt–Sim (PAS) domain, followed by an autokinase domain, a response regulator domain, and a C-terminal c-di-GMP phosphodiesterase (PDE) domain. Autophosphorylation of TolR in response to toluene exposure initiated an intramolecular phosphotransfer to the response regulator domain that resulted in c-di-GMP degradation. The TolR protein was engineered as a functional sensor histidine kinase (TolRSK) and an independent response regulator (TolRRR). This classic two-component system (CTCS) operated less efficiently than TolR, suggesting that TolR was evolved as a HTCS to optimize signal transduction. Our results suggest that TolR enables Azoarcus sp. CIB to adapt to toxic aromatic hydrocarbons under anaerobic conditions by modulating cellular levels of c-di-GMP. This is an additional role for c-di-GMP in bacterial physiology.

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Bauer, Carl, Sylvie Elsen, Lee R. Swem, Danielle L. Swem i Shinji Masuda. "Redox and light regulation of gene expression in photosynthetic prokaryotes". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 358, nr 1429 (29.01.2003): 147–54. http://dx.doi.org/10.1098/rstb.2002.1189.

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All photosynthetic organisms control expression of photosynthesis genes in response to alterations in light intensity as well as to changes in cellular redox potential. Light regulation in plants involves a well–defined set of red– and blue–light absorbing photoreceptors called phytochrome and cryptochrome. Less understood are the factors that control synthesis of the plant photosystem in response to changes in cellular redox. Among a diverse set of photosynthetic bacteria the best understood regulatory systems are those synthesized by the photosynthetic bacterium Rhodobacter capsulatus . This species uses the global two–component signal transduction cascade, RegB and RegA, to anaerobically de–repress anaerobic gene expression. Under reducing conditions, the phosphate on RegB is transferred to RegA, which then activates genes involved in photosynthesis, nitrogen fixation, carbon fixation, respiration and electron transport. In the presence of oxygen, there is a second regulator known as CrtJ, which is responsible for repressing photosynthesis gene expression. CrtJ responds to redox by forming an intramolecular disulphide bond under oxidizing, but not reducing, growth conditions. The presence of the disulphide bond stimulates DNA binding activity of the repressor. There is also a flavoprotein that functions as a blue–light absorbing anti–repressor of CrtJ in the related bacterial species Rhodobacter sphaeroides called AppA. AppA exhibits a novel long–lived photocycle that is initiated by blue–light absorption by the flavin. Once excited, AppA binds to CrtJ thereby inhibiting the repressor activity of CrtJ. Various mechanistic aspects of this photocycle will be discussed.

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Huang, Jun, i Dibyendu K. Sasmal. "TCR-pMHC bond length controls TCR ligand discrimination". Journal of Immunology 202, nr 1_Supplement (1.05.2019): 184.10. http://dx.doi.org/10.4049/jimmunol.202.supp.184.10.

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Abstract T-cell receptors (TCRs) detect specifically and sensitively a small number of agonist peptide-major histocompatibility complexes (pMHCs) from an ocean of structurally similar self-pMHCs to trigger antigen-specific adaptive immune responses. Despite intense efforts, the mechanism underlying TCR ligand discrimination remains a major unanswered question in immunology. Here we show that a TCR discriminates between closely related peptides by forming TCR-pMHC bonds with different lengths, which precisely control the accessibility of CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation. Using in situ fluorescence resonance energy transfer (FRET), we measured the intermolecular length of single TCR-pMHC bonds and the intramolecular distance of individual TCR-CD3ζ complexes at the membrane of live primary T cells. We found that an agonist forms a short TCR-pMHC bond to pull the otherwise sequestered CD3ζ off the inner leaflet of the plasma membrane, leading to full exposure of its ITAMs for strong phosphorylation. By contrast, a structurally similar weaker peptide forms a longer bond with the TCR, resulting in partial dissociation of CD3ζ from the membrane and weak phosphorylation. Furthermore, we found that TCR-pMHC bond length determines 2D TCR binding kinetics and affinity, T-cell calcium signaling and T-cell proliferation, governing the entire process of signal reception, transduction and regulation. Thus, our data reveal the fundamental mechanism by which a TCR deciphers the structural differences between foreign antigens and self-peptides via TCR-pMHC bond length to initiate different TCR signaling for ligand discrimination.

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46

Bender, Kyle W., Raymond E. Zielinski i Steven C. Huber. "Revisiting paradigms of Ca2+ signaling protein kinase regulation in plants". Biochemical Journal 475, nr 1 (5.01.2018): 207–23. http://dx.doi.org/10.1042/bcj20170022.

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Calcium (Ca2+) serves as a universal second messenger in eukaryotic signal transduction. Understanding the Ca2+ activation kinetics of Ca2+ sensors is critical to understanding the cellular signaling mechanisms involved. In this review, we discuss the regulatory properties of two sensor classes: the Ca2+-dependent protein kinases (CPKs/CDPKs) and the calcineurin B-like (CBL) proteins that control the activity of CBL-interacting protein kinases (CIPKs) and identify emerging topics and some foundational points that are not well established experimentally. Most plant CPKs are activated by physiologically relevant Ca2+ concentrations except for those with degenerate EF hands, and new results suggest that the Ca2+-dependence of kinase activation may be modulated by both protein–protein interactions and CPK autophosphorylation. Early results indicated that activation of plant CPKs by Ca2+ occurred by relief of autoinhibition. However, recent studies of protist CDPKs suggest that intramolecular interactions between CDPK domains contribute allosteric control to CDPK activation. Further studies are required to elucidate the mechanisms regulating plant CPKs. With CBL–CIPKs, the two major activation mechanisms are thought to be (i) binding of Ca2+-bound CBL to the CIPK and (ii) phosphorylation of residues in the CIPK activation loop. However, the relative importance of these two mechanisms in regulating CIPK activity is unclear. Furthermore, information detailing activation by physiologically relevant [Ca2+] is lacking, such that the paradigm of CBLs as Ca2+ sensors still requires critical, experimental validation. Developing models of CPK and CIPK regulation is essential to understand how these kinases mediate Ca2+ signaling and to the design of experiments to test function in vivo.

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Cheng, Haiyun, Jim A. Rogers, Nancy A. Dunham i Thomas E. Smithgall. "Regulation of c-Fes Tyrosine Kinase and Biological Activities by N-Terminal Coiled-Coil Oligomerization Domains". Molecular and Cellular Biology 19, nr 12 (1.12.1999): 8335–43. http://dx.doi.org/10.1128/mcb.19.12.8335.

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ABSTRACT The cytoplasmic protein-tyrosine kinase Fes has been implicated in cytokine signal transduction, hematopoiesis, and embryonic development. Previous work from our laboratory has shown that active Fes exists as a large oligomeric complex in vitro. However, when Fes is expressed in mammalian cells, its kinase activity is tightly repressed. The Fes unique N-terminal sequence has two regions with strong homology to coiled-coil-forming domains often found in oligomeric proteins. Here we show that disruption or deletion of the first coiled-coil domain upregulates Fes tyrosine kinase and transforming activities in Rat-2 fibroblasts and enhances Fes differentiation-inducing activity in myeloid leukemia cells. Conversely, expression of a Fes truncation mutant consisting only of the unique N-terminal domain interfered with Rat-2 fibroblast transformation by an activated Fes mutant, suggesting that oligomerization is essential for Fes activation in vivo. Coexpression with the Fes N-terminal region did not affect the transforming activity of v-Src in Rat-2 cells, arguing against a nonspecific suppressive effect. Taken together, these findings suggest a model in which Fes activation may involve coiled-coil-mediated interconversion of monomeric and oligomeric forms of the kinase. Mutation of the first coiled-coil domain may activate Fes by disturbing intramolecular coiled-coil interaction, allowing for oligomerization via the second coiled-coil domain. Deletion of the second coiled-coil domain blocks fibroblast transformation by an activated form of c-Fes, consistent with this model. These results provide the first evidence for regulation of a nonreceptor protein-tyrosine kinase by coiled-coil domains.

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Haruta, T., T. Sawa, Y. Takata, T. Imamura, Y. Takada, H. Morioka, G. H. Yang i M. Kobayashi. "An extracellular domain of the β subunit is essential for processing, transport and kinase activity of insulin receptor". Biochemical Journal 305, nr 2 (15.01.1995): 599–604. http://dx.doi.org/10.1042/bj3050599.

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The extracellular portion of the insulin receptor (IR) beta-subunit has four cysteine and four asparagine residues which are potentially involved in disulphide bond formation between the alpha- and beta-subunits and N-linked glycosylation respectively. However, the function of this portion is not fully understood. In order to investigate the role of the extracellular domain of beta-subunit, we created a deletion mutant of IR cDNA which lacked 47 amino acid residues encoded by 141 bp corresponding to exon 13 of the IR gene. Insulin binding and surface labelling of COS 7 cells transiently expressing the mutant insulin receptors (IR delta Ex13) showed that the mutated receptors were not expressed on the cell surface. However, immunoblot analysis showed that uncleaved form (190 kDa) of the mutant receptors were intracellularly expressed. Deglycosylation with endoglycosidase H showed that the mutant receptors had mainly high-mannose oligosaccharide chains. The mutant IRs bound with high affinity to lentil lectin but with low affinity to wheat germ agglutinin. Therefore, it is suggested that misfolding of the mutant receptors inhibits transport to the Golgi apparatus where processing of oligosaccharide chains, as well as proteolytic cleavage into subunits, takes place. The binding affinity of the mutant receptors for insulin was 50% of normal. Furthermore, insulin-stimulated autophosphorylation of IR delta Ex13 was markedly impaired. These data provide the evidence for a critical role of the extracellular domain of IR beta-subunit for processing and transport as well as the intramolecular signal transduction to activate IR tyrosine kinase.

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Zhang, Yan-Liang, John A. Frangos i Mirianas Chachisvilis. "Mechanical stimulus alters conformation of type 1 parathyroid hormone receptor in bone cells". American Journal of Physiology-Cell Physiology 296, nr 6 (czerwiec 2009): C1391—C1399. http://dx.doi.org/10.1152/ajpcell.00549.2008.

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The molecular mechanisms by which bone cells transduce mechanical stimuli into intracellular biochemical responses have yet to be established. There is evidence that mechanical stimulation acts synergistically with parathyroid hormone PTH(1-34) in mediating bone growth. Using picosecond time-resolved fluorescence microscopy and G protein-coupled receptor conformation-sensitive fluorescence resonance energy transfer (FRET), we investigated conformational transitions in parathyroid hormone type 1 receptor (PTH1R). 1) A genetically engineered PTH1R sensor containing an intramolecular FRET pair was constructed that enabled detection of conformational activity of PTH1R in single cells. 2) The nature of ligand-dependent conformational change of PTH1R depends on the type of ligand: stimulation with the PTH(1-34) leads to conformational transitions characterized by decrease in FRET efficiency while NH2-terminal truncated ligand PTH(3-34) stimulates conformational transitions characterized by higher FRET efficiencies. 3) Stimulation of murine preosteoblastic cells (MC3T3-E1) with fluid shear stress (FSS) leads to significant changes in conformational equilibrium of the PTH1R in MC3T3-E1 cells, suggesting that mechanical perturbation of the plasma membrane leads to ligand-independent response of the PTH1R. Conformational transitions induced by mechanical stress were characterized by an increase in FRET efficiency, similar to those induced by the NH2-terminal truncated ligand PTH(3-34). The response to the FSS stimulation was inhibited in the presence of PTH(1-34) in the flow medium. These results indicate that the FSS can modulate the action of the PTH(1-34) ligand. 4) Plasma membrane fluidization using benzyl alcohol or cholesterol extraction also leads to conformational transitions characterized by increased FRET levels. We therefore suggest that PTH1R is involved in mediating primary mechanochemical signal transduction in MC3T3-E1 cells.

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Lee, Seung-Yub, Fubo Liang, Xiao-Ling Guo, Laiping Xie, Sean M. Cahill, Michael Blumenstein, Heyi Yang, David S. Lawrence i Zhong-Yin Zhang. "Design, Construction, and Intracellular Activation of an Intramolecularly Self-Silenced Signal Transduction Inhibitor". Angewandte Chemie International Edition 44, nr 27 (4.07.2005): 4242–44. http://dx.doi.org/10.1002/anie.200462004.

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